U.S. patent application number 11/381690 was filed with the patent office on 2006-11-02 for inotropic orthorhythmic cardiac stimulator.
This patent application is currently assigned to Medtronic, Inc.. Invention is credited to Fred Zacouto.
Application Number | 20060247701 11/381690 |
Document ID | / |
Family ID | 34524993 |
Filed Date | 2006-11-02 |
United States Patent
Application |
20060247701 |
Kind Code |
A1 |
Zacouto; Fred |
November 2, 2006 |
Inotropic Orthorhythmic Cardiac Stimulator
Abstract
Programmable and implantable automatic heart stimulation device
(OIST) for controlling the heart, accompanied by a marked increase
in the contractility of the myocardial cells on each beat produced
by an optimized post-extrasystolic potentiation effect. The OIST
does not cause lasting fatigue of the myocardium, markedly
increases the coronary rate instantaneously and durably, causes
dilatation of the walls to regress and opposes thromboses and
arrhythmia. The OIST creates a genetic involution of the
pathological process either by the mere effect of the
mechanosensitivity of specific genetic expressions or by the
addition of partial autologous cell dedifferentiation, obtained by
original genetic manipulation which induces physiological an
anatomical regeneration. This method also allows physiological
auto-contractile living arterial stents, in particular coronary
stents to be created, as well as the grafting of dedifferentiated
myocardial cells.
Inventors: |
Zacouto; Fred; (Paris,
FR) |
Correspondence
Address: |
MEDTRONIC, INC.
710 MEDTRONIC PARK
MINNEAPOLIS
MN
55432-9924
US
|
Assignee: |
Medtronic, Inc.
Minneapolis
MN
|
Family ID: |
34524993 |
Appl. No.: |
11/381690 |
Filed: |
May 4, 2006 |
Current U.S.
Class: |
607/9 |
Current CPC
Class: |
C12N 2529/00 20130101;
C12N 5/0657 20130101; A61K 35/12 20130101; C12N 13/00 20130101 |
Class at
Publication: |
607/009 |
International
Class: |
A61N 1/362 20060101
A61N001/362 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 6, 2003 |
FR |
0313055 |
Feb 20, 2004 |
FR |
0401736 |
Claims
1. Device for stimulating and/or potentiating the heart muscle
and/or the myocardial cells, allowing a significant increase in the
hemodynamic performance of the heart and/or the treatment of
tachycardia, tachyarrhythmia or auricular fibrillation, comprising:
means for the automatic acquisition (1, 2, 3) of the heart rhythm
and optionally of its origin, for detecting, in particular, the
interval between at least the last two waves R (induced or
spontaneous) of the cardiac cycle just completed; means for the
precise acquisition of cardiac hemodynamics; means (4) for
determining, continually or periodically, in real time, the
duration of the electrical refractory period (ERZ) following the
last wave R of said cycle; means for evaluating at least one
parameter relating to the functional cell state of the myocardium;
and means for sending (8, 9, 10) wherein said means for sending are
subordinate to said evaluating means, for sending substantially
without delay at the end of said refractory period (ERZ), at least
one of a paired stimulating pulse and a coupled stimulating pulse
adapted to said functional cell state.
2. A device according to claim 1, wherein said means for evaluating
determines the position and duration of a critical zone effective
in targeting ECZ, which is placed immediately after the end of the
electrical refractory zone and terminates at the end of a
refractory zone of maximum myocardial contraction MMRZ, the
transmission of said stimulating pulse intervening in said ECZ
zone.
3. A device according to either claim 2, wherein said means for
evaluating detects the excitability threshold of the myocardium
during one or each cardiac cycle and periodically.
4. A device according to claim 1, wherein the means for sending (8,
9, 10) sends a burst of stimulating pulses substantially at the end
of said refractory period (ERZ), wherein the duration of the burst
and the pulse repetition interval apply a stimulating pulse of the
burst to the heart substantially without delay after the end of
said refractory period.
5. A device according to claim 4, wherein the means (4) for
determining the duration of the electrical refractory period (ERZ)
are sensitive without delay to the detection of the pulse of a
burst which triggered a complex (R').
6. A device according to claim 1, wherein, in the event that the
device generates a single stimulating pulse instead of a burst, the
means (4) for determining the duration of the refractory zone are
arranged so as to acquire, by scanning a second pulse, the
substantially exact duration of the refractory zone, this scanning
being carried out during one of a plurality of preceding and
current cardiac cycles.
7. A device for stimulating and/or potentiating the heart muscle
and/or the myocardial cells, for significantly increasing the
hemodynamic performance of the heart and/or the treatment of
auricular tachycardia, tachyarrhythmia or fibrillation comprising:
means for the precise acquisition of the cardiac hemodynamics (5,
6) and comprising a means for instantaneous detection of the
maximum myocardial refractory zone (MMRZ) at a precise location of
the myocardium; and means for sending at least one stimulating
pulse and preferably a burst of stimulating pulses from the local
region in which the occurrence of the zone MMRZ is detected.
8. A process for stimulating the heart muscle to allow a
significant increase in hemodynamic performance of the heart and/or
the treatment of tachycardia comprising the following steps:
providing a permanently implanted heart stimulation device and,
with the aid of this device; automatically acquiring the heart
rhythm so as to obtain an interval between at least the last two
R-waves, regardless whether they comprise induced R-waves or
spontaneous R-waves, of the just completed cardiac cycle;
determining in real time, in particular on request, preferably
continually, the duration of the electrical refractory period (ERZ)
following the last wave R of said cycle; and applying at least one
cardiac stimulation pulse substantially without delay at the end of
said refractory period (ERZ).
9. A process for inotropic cardiac stimulation according to claim
8, characterized by the following steps: detecting the electrical
heart signals, including premature extrasystoles, via at least one
of a pair of extracardiac electrodes implanted in communication
with a heart; determining whether a detected extrasystole comprises
a possible risk to a patient wherein said possible risk includes
one of a premature extrasystole and a ventricle-originating
extrasystole; and transmitting a stimulating pulse train
substantially instantaneously in the region of the at least one of
the pair of extracardiac electrodes.
10. A process for treating acute or severe heart failure wherein:
automatically acquiring a heart rhythm including at least an
interval between at least a recent pair of R-waves, regardless
whether either of the recent pair is an induced R-wave or a
spontaneous R-wave; determining a duration of an electrical
refractory period (ERZ) following the last R-wave of said cycle;
applying to the heart at least one of a stimulating pulse and a
stimulating pulse burst substantially without delay following the
end of the electrical refractory period (ERZ), wherein the duration
of the pulse burst includes, in view of the pulse repetition
interval in the burst, a capturing pulse within the pulse burst
substantially without delay after the end of the refractory period;
in the event that initial improvement in cardiac performance is
observed, repeating the foregoing steps of the process for a series
of at least three cardiac cycles but wherein in the absence of an
initial improvement in cardiac performance is observed,
discontinuing the steps of the process.
11. A process according to claim 106, wherein the total mechanical
performance of the heart, in particular its blood flow and/or the
variation in ventricular volume is compared, on the one hand,
before carrying out the steps of the process and, on the other
hand, after carrying out the steps of the process and, if the
increase in heart performance is greater than 15%, the steps of the
process are carried out again.
12. A process for cardiac resuscitation in a patient suffering from
severe or critical heart failure wherein: automatically acquiring a
heart rhythm including an interval between at least the last two
R-waves of a cardiac cycle; determining the duration of an
electrical refractory period (ERZ) following the last R-wave of
said cycle; applying to a heart at least one of a stimulating pulse
and a stimulating pulse burst substantially without delay at the
end of the refractory period (ERZ), wherein the duration of the
burst being such that, in view of the pulse repetition interval in
the burst, a stimulating pulse of the burst is sent to the heart
substantially without delay after the end of the refractory period;
repeating the foregoing steps of the process for a series of at
least three cardiac cycles if an initial improvement in cardiac
performance is observed; and continuing to repeat the foregoing
steps until a progressive improvement in detectable cardiac
performance is achieved.
13. A process for in vitro stimulation of cells intended to be
implanted in the heart, said process comprising the following
steps: obtaining and cultivating, in vitro, regeneration cells,
said cells comprising a form of small groups or confluent cultures,
so as to be in mutual contact; placing the confluent cells in
electrically conductive contact with one another and optionally
with the cells of a previously taken myocardial tissue and with an
electrical stimulation device; periodically sending electrical
pulses to said cultivated cells; and detecting the electrical
depolarization responses of the cells and/or membrane potentials,
and/or electrical refractory zones.
14. A process according to claim 13. wherein the stimulation
comprises a simple electrical stimulation at a rhythm preferably
approximating a normal heart rhythm, followed after an initial
period by one or a paired cardiac stimulation and a coupled cardiac
stimulation regimen, once the groups of cells in culture are
synchronized so as to manifest an electrical refractory period, in
particular a period relatively close to that of the cells of the
heart intended to receive the cells.
15. Process according to claim 13, wherein the cells have been
modified so as to over-express telomerase or Sir2 protein.
16. A process according to claim 13, wherein the cells comprise one
of an arterial segment and a stent, wherein said segment and stent
include characteristics in common with on of a particular target
application, said target application consisting of one of the
group: a coronary site, an aortic site, a carotid site, a renal
site, a femoral site; and wherein the segment or stent further
includes a coating or colonization of cells obtained by the process
of claim 13.
17. Arterial segment or stent according to claim 16, wherein the
segment or stent further comprises additional structure including
at least a portion of an expansible mesh material, said mesh
material configured to support a plurality of different cell
layers, said different cell layers selected from the group
consisting of: an endoartery layer, a myoartery layer, a periartery
layer, wherein said segment or stent is configured to allow
spontaneous and progressive progressive widening of an interior
lumen and to allow creation of vascularization, wherein said
vascularization nourishes at least the myoarterial layer.
18. A biological cardiac pacemaker comprising partially
dedifferentiated cardiac auto-rhythmic cells or tissues according
to claim 13, which includes a plurality of autologous or homologous
cells, wherein said cells originate from a recipient organism and
wherein said cells are intended to be implanted in one of a heart
and in a defective region of the heart.
19. A process for preparing living cells, in particular vegetable,
animal and human cells, which can be reimplanted prophylactically
or therapeutically, wherein a nucleus of a dedifferentiated cell is
transported in an oocyte, preferably an unfertilized or recently
fertilized oocyte from a homologous or heterologous mammal,
previously preferably completely or partially freed of its nucleus,
so as to induce a stage of mitosis of the transferred nucleus, in
that this nucleus is removed during the mitosis and before the end
of it, then this nucleus which is partially dedifferentiated in
mitosis at this stage is introduced into a cell, preferably after
some part or the totality of its nucleus or nuclei have been
removed from it, so as to induce and terminate the differentiating
nuclear division thereof and to form a cell strain or a tissue at a
less advanced stage of differentiation than said differentiated
cell.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This patent disclosure claims priority to and all benefit
from international application number PCT FR 2004/002767 and French
national applications; namely serial number 0313055 filed Nov. 6,
2003 and serial number 0401736 filed Feb. 20, 2004, the contents of
the foregoing are hereby fully incorporated herein by reference in
their respective entirety.
[0002] The invention relates to a device for electrical stimulation
of the heart for, in particular, improving hemodynamic performance,
performance of the heart cells and, in particular, blood flow, in
particular in patients suffering from heart failure or from
tachycardia or arrhythmia, and in particular from left or right,
systolic, diastolic or global, severe or acute heart failure.
[0003] The invention also relates to a process for controlling such
a device.
[0004] The invention further relates to a process for electrical
stimulation of the heart and for heart cell improvement using such
a device, in particular in patients suffering from heart failure or
tachycardia or arrhythmia and in particular from acute, left, right
or global cardiac failure.
[0005] Up until now, automatic heart stimulating devices, also
known as pacemakers, were basically intended to replace or regulate
the spontaneous electrogenesis of heart muscle activation.
[0006] A significant step has been taken in the control and
reduction of isolated tachycardia, tachyarrhythmia or extrasystoles
in the process and devices described in the Zacouto patents U.S.
Pat. No. 4,052,991 and U.S. Pat. No. 3,857,399. These improvements
enabled the coupling intervals of electrical stimulation, in
particular, to be modified as a function of the variable duration
of the previous cycle or cycles, for example as a percentage of
this duration. These improvements also allowed the stimulations to
be transmitted in a burst and in gradients. They also allowed
differential marking of the spots of local detection and
stimulation on the electrocardiogram.
[0007] Paired stimulation (PST) or coupled stimulation (CST) and
optimum inotropic stimulation (OIST) attempts to induce, manually
or automatically, a periodic succession of myocardial inhibition
and stimulation preferably with parameters for obtaining maximum
hemodynamics and anti-rhythmic protection. The OIST basically
allows greater mobilization of the reserves and acquisitions of
energy from the myocardium which are generally greater, the more
fatigued the myocardium (Wayne Cooper: Postextrasystolic
Potentialisation, Circulation, vol. 88, no. 6, 2962, Dec. 1993)
such as, for example, increased activation of a pentose cycle in
addition to the Krebs cycle (hexoses) and/or potentiated and
resynchronized activation of specific ion channels and
transmembrane electrons, the increase in intracellular
concentrations and liberations of calcium ions, secretions of
vaso-active or myo-active peptides and changes of specific local
genetic expressions, translations and transductions of adaptations
to potentiated biochemical myocardial energy of the "sporting
heart" type. This instantaneous, significant and lasting
potentiation, without a known limit over time, in contractility
after specific extrasystoles is well known to cardiologists under
the name of post-extrasystolic potentiation (PESP). PESP is a
frequent natural phenomenon which demonstrates the possibility of
further mobilizing the acquisition and the expenditure of
myocardial energy reserves which often remain inhibited during
failures thereof (apart from specific ectopic tachycardia). The
continuation of the PESP, even in the case of acute grave failure
of the myocardium (example: pulmonary edema after recent previous
extended infarction of the myocardium) or chronic myocardium
failure (Classificat. New-York Heart Assoc., classes 2 to 4) shows
the possibility of using PST in these clinical cases.
[0008] However, paired stimulation (PST), which has been known, in
particular, since 1964 and widely tested in animals and in several
clinical trials to reduce or better withstand specific tachycardia
and myocardial failures (for example: F. Zacouto et coil., Paris,
Nouv. Presse Med. 1974, 3, No. 22, p. 1448), is still virtually
never used in cardiology. This is due to the use of heart
stimulation and detection equipment which is tragically inadequate
as it is incapable of continuously targeting the narrow critical
zones and is often unstable in each cardiac cycle (CC) which it is
however essential to reach in order to carry out optimum continuous
effective PST which is economical in oxygen and
anti-arrhythmic.
[0009] In general, currently used devices do not allow the
hemodynamic performance of the heart muscle to be durably improved
by electrical stimulation, particularly in the case of patients in
whom this performance is significantly reduced, in particular in
those with grave heart failure.
[0010] The phenomenon of post-extrasystolic potentiation (PESP) has
been observed since the 19th century.
[0011] Thus, the applicant was able to obtain a temporary
improvement in hemodynamics in two patients suffering from acute
left ventricular failure, by coupling, after initial manual
adjustment, a paired stimulation comprising bursts of successive
stimulating pulses which are brought together in the same coupled
cardiac cycle on the wave R toward the end of the refractory zone
(F. Zacouto et al., Paris, Nouv. Presse Med. 1974, 3, No. 22, p.
1448).
[0012] Considerable research was then carried out into the
phenomenon of post-extrasystolic potentiation in an attempt to
benefit from the improvement in the mechanical contraction
triggered by the transmission of electrical stimulations inducing a
stimulated extrasystole (see, for example, the documents U.S. Pat.
No. 3,939,844 and U.S. Pat. No. 5,213,098). Despite considerable
work over a long period, however, the researchers finally came to
the conclusion that the problem of establishing, in a durable and
effective manner, myocardial contractility potentiation by paired
stimulation could not be solved and, even though this principle
looked promising, the results of the trials were discouraging (see,
for example, N. Wayne Cooper: Postextrasystolic Potentialisation,
Circulation, vol. 88, no. 6, 2962, Dec. 1993).
[0013] These failures can be explained, in particular, by the fact
that the electrical refractory functional zones (ERZ) and
myocardial refractory functional zones (MRZ) and the corresponding
metabolic reactions can vary significantly during each cycle, in
particular in the case of myocardium suffering or of irregular
rhythm disorders.
[0014] More recently, suggestions have been made regarding the
creation of apparatus capable of sending to the heart paired or
coupled bursts of pulses intended either to induce a sensitization
action on the myocardium during the electrical refractory period,
according to a hypothesis, or to generate, just after the end of
the electrical refractory period, an electrosystole intended to
induce post-extrasystolic potentiation during a subsequent systole.
Various documents deal with research into potentiation, such as WO
02/53206 and WO 03/20364.
[0015] It was found during this research, however, that paired or
coupled stimulation is not compatible with arrhythmia or
tachyarrhythmia, which is common, in particular, in patients
suffering from cardiac failure, when it does not induce them itself
in hearts that are already unstable.
[0016] Faced with problems and discouraging conclusions from the
research, the present invention proposes to provide a device and
processes for durably and significantly improving the hemodynamic
performance of the heart by electrical stimulation.
[0017] A further object of the invention is to treat arrhythmia or
tachycardia, even tachycardia which are recurrent or cannot quickly
be reduced by anti-tachycardic pacemakers (Zacouto, U.S. Pat. No.
3,857,399 and U.S. Pat. No. 4,052,991), even in patients suffering
from cardiac failure, and to instantaneously improve hemodynamics,
whether or not the tachycardia is reduced.
[0018] In its general scope, the invention proposes to improve a
heart muscle stimulating device allowing a significant increase in
the hemodynamic performance of the heart and/or the treatment of
tachycardia comprising a device which is preferably implanted
permanently and comprises:
[0019] means for automatic acquisition of the heart rhythm, for
detecting, in particular, the interval between at least the last
two waves R (induced or spontaneous) of the cardiac cycle just
completed,
[0020] means for determining, preferably in real time, the duration
of the electrical refractory period (ERZ) following the last wave R
of said cycle,
[0021] and means for sending at least one stimulating pulse,
substantially without delay toward or at the end of said refractory
period (ERZ).
[0022] The coupling stimulating pulse or that pulse of the burst
which stimulates the heart generates a wave (R') which does not
cause a mechanical reaction but induces an additional electrical
refractory zone (RZ) contributing to the desired inotropic and
anti-arrhythmic effect.
[0023] The invention relates to a device for stimulating and/or
potentiating the heart muscle and/or the myocardial cells, allowing
a significant increase in the hemodynamic performance of the heart
and/or the treatment of tachycardia, tachyarrhythmia or auricular
fibrillation, comprising:
[0024] means for the automatic acquisition of the heart rhythm and,
optionally of its origin, for detecting, in particular, the
interval between at least the last two waves R (induced or
spontaneous) of the cardiac cycle just completed,
[0025] means for the precise acquisition of the cardiac
hemodynamics,
[0026] means for determining, continually in real time, the
duration of the electrical refractory period (ERZ) following the
last wave R of said cycle,
[0027] means for evaluating at least one parameter relating to the
functional cell state of the myocardium, [0028] and means which are
subordinate to said evaluating means for sending at least one
paired or coupled stimulating pulse adapted to said functional cell
state substantially without delay at the end of said refractory
period (ERZ).
[0029] In a particularly preferred manner, said evaluation means
determine an effective critical zone (ECZ) to target, which is
placed immediately after the end of the electrical refractory zone
and terminates at the end of a maximum myocardial contraction
refractory zone (MMRZ), the transmission of said stimulating pulse
occurring in said zone (ECZ), if it is present and targetable and
does not induce untreatable arrhythmia. In the latter case, means
for automatically retarding the zone ECZ, for example by 20 ms to
20 ms, are provided, while the hemodynamics and metabolic
consumption of the myocardium are monitored.
[0030] Preferably, said evaluation means attempt to detect or check
the myocardium excitability threshold during each cycle.
[0031] Preferably, according to the invention, the device is
arranged so as to determine the duration of said electrical
refractory period (ERZ) during each cycle and preferably in real
time.
[0032] Advantageously, the refractory zone is determined in a part
of the heart into which the stimulating pulse or burst is sent, for
example by using the same electrodes for detection and stimulation,
or very close electrodes.
[0033] In an advantageous embodiment, the means send, substantially
at the end of said refractory period (ERZ), a burst of stimulating
pulses, the duration of the burst and the pulses repetition
interval being such that a stimulating pulse of the burst is sent
to the heart substantially without delay after the end of said
refractory period.
[0034] Preferably, the stimulating pulse sent toward or at the end
of the refractory period is sent, almost without delay, for example
between 10 and 20 ms after the end of the refractory zone ERZ. In
the case of a burst, however, it is necessary for the beginning of
the burst to be produced within and toward the end of the
refractory period.
[0035] It is found that the contractility and hemodynamics
generated by at least one of the stimulating pulses of the burst
can be potentiated by a mere implanted device, in particular in the
case of acute or severe cardiac failure.
[0036] At the same time, a significant permanent reduction of the
ventricular rhythm and potentiation of heart contractility are
obtained in tachycardic hearts.
[0037] As a particular result, significantly more powerful cardiac
contractions are obtained but do not lead to an unacceptable
over-consumption of oxygen by the heart, because the increase in
oxygen consumption is compensated by the concomitant increase in
the coronary flows and over-compensated by the gain in
contractility.
[0038] The device is thus capable of carrying out optimum inotropic
paired or coupled stimulation, hereinafter called OIST.
[0039] The duration of the refractory zone ERZ of the current cycle
can be determined from characteristics of the preceding cycle or
even from earlier cycles. For example it can be evaluated a priori
as a percentage of the earlier cycle duration, which percentage
increases if the duration of the cycle is decreasing. For example,
the percentage will be from 25 to 30% in the case of a rhythm of 60
p/mn and from 50 to 80% in the case of a rhythm of 120 p/mn.
[0040] The duration of the refractory zone can be evaluated by any
other means already known to cardiologists, for example by
progressive scanning of an electrical pulse in a burst which is
retarted from cycle to cycle until a generated electrosystole is
acquired. The duration ERZ obtained can thus be used during one or
more following cycles to transmit the stimulating pulse or burst of
pulses.
[0041] If the device generates a single stimulating pulse instead
of a burst, the means (4) for determining the duration of the
refractory zone are arranged so as to acquire, by scanning a second
pulse, the substantially exact duration of the refractory zone,
this scanning being carried out, for example, during the preceding
or current cardiac cycles.
[0042] If a burst of stimulating pulses is used, it will preferably
begin just before the estimated end of the refractory period ERZ,
and the duration of this burst and consequently the number of
stimulating pulses will advantageously be such that a stimulating
pulse can occur very quickly after the end of said refractory
period.
[0043] These means for determining the duration of a refractory
zone of the heart are known to cardiologists.
[0044] In a variation of the invention, if the stimulation at the
end of the refractory period ERZ is carried out by transmission of
a burst of pulses, the device can transmit the burst substantially
before the estimated end of the refractory period ERZ and detect
without delay in the same cycle, preferably at the same location of
the heart, which of the pulses of the burst induces an
electrosystole R' for a given stimulation amplitude, and this
provides the duration ERZ which has just elapsed. This detected
duration also enables the likely duration of the refractory zone
ERZ of the following cycle to be determined.
[0045] Preferably there are provided anti-tachycardic stimulation
means and extrasystole-sensitive means for automatically stopping
said stimulation if excessive hemodynamic instability or electrical
arrhythmia corresponding to predetermined criteria occur.
[0046] In a developed embodiment, the determination of the
refractory zone ERZ of the cycle to come can be refined by allowing
for one or more detected parameters while allowing for the
functional and rhythmic stability of the heart.
[0047] These parameters can be, in particular:
[0048] duration of the earlier or current cycle or cycles,
[0049] hemodynamic parameters, metabolic consumption and
excitability threshold over a specific number of comparable
successive contractions, by comparison with thresholds.
[0050] In the event of significant discordance between, for
example, the zone ERZ calculated using the ratios between the
intervals QT and the actual intervals RR of the patient, as known
in cardiology, and the measured zone ERZ, the myocardium can
undergo a metabolic change which can precede either a grave
arrhythmia if the ERZ is decreasing or re-establishment of function
if the ERZ is increasing.
[0051] The apparatus monitors and distinguishes between these two
cases and reacts instantaneously according to programming. In the
case of grave arrhythmia, for example, stimulation is stopped or
the stimulation parameters are modified.
[0052] The burst of stimulating pulses may be advanced or retarded
relative to an estimate of the refractory zone and/or the pulse
interval in the burst and/or the reduced or increased pulse
amplitude, the device having automatic acquisition means, in
particular by obtaining the intracardiac ECG for determining which
stimulating pulse in the burst triggered the wave R' and
consequently by possibly modifying the burst.
[0053] A device of this type will be particularly indicated for
reduction of tachycardia, including sinusoidal tachycardia, in
patients suffering from cardiac failure.
[0054] Preferably, the device comprises means which are sensitive
to spontaneous or stimulated waves R and/or to the determination of
the electrical and mechanical refractory zones, in particular by
scanning all of the burst or only within this burst and/or means
for the determination without delay of the heart excitability
thresholds, for example by providing stimulating pulses of variable
intensity, including subliminal pulses for allowing the measurement
thereof. It is also proposed to be able to control the stimulator
as a conventional anti-tachycardic auto-rhythmic stimulator
reacting to the extrasystoles and to be able to automatically stop
the programmed OIST on occurrence of excessive hemodynamic
instability. In the event of excessive instability of the
refractory zones or myocardium excitability thresholds or the two
simultaneously, the durations and/or the number and/or the voltage
of the pulses of the bursts can, for example, be increased or the
stoppage of operation from a threshold can be programmed.
[0055] Preferably, the device is characterized in that it further
comprises means for very precise acquisition of the cardiac
hemodynamics.
[0056] These means are known per se and preferably comprise one or
more intracardiac pressure sensors or such sensors disposed in the
vicinity. Preferably, sensors for determining variations in heart
volume, for example known, in particular juxta- and intracardiac
electrical impedance proximity sensors, are also used for acquiring
precise pressure/volume curves of cardiac contraction.
[0057] In a perfected embodiment of the invention, a device
according to the invention which is implantable or even external
and non-implantable, can comprise, in addition to the rhythm
acquisition means, means for determining the duration of refractory
zone, and pulse or burst transmission means as described above,
means sensitive to the precise acquisition of the hemodynamics for
determining the variations in efficacy of the hemodynamics, these
means being capable of controlling the transmission and optionally
the parameters of the pulse or of the burst and/or the
administration of an external perfused dose of medicament which is
controlled or based on an implanted medicament reservoir until a
degree of hemodynamic performance is obtained which is, for
example, programmed or determined in advance, or in a manner
resembling that which produced the most favorable hemodynamics for
the patient at a given moment.
[0058] Various aspects of the invention will now be described.
[0059] Control of OIST
[0060] In general and particularly in the case of severe or acute
failure, the present variations in the electrical refractory zones
(ERZ), the mechanical refractory zones (MRZ), the excitability
thresholds, the hemodynamics and the metabolic behavior cannot
themselves anticipate the development of the intramyocardial
functional state of the electromechanical coupling (EMC). The
electromechanical coupling (EMC) can be observed only by precise,
individualized specific temporal comparisons that can be provided
by the device according to the invention, in particular in the form
of an analyzing simulator (ASIM), without which rapid myocardial
failures can remain unpredictable and unstoppable by OIST.
[0061] Continuous Optimum Maintenance of OIST Parameters Relative
to Variations in the Myocardial Excitability Thresholds
[0062] In a preferred embodiment of the invention, the excitability
threshold of the heart is monitored continuously by means of a
periodic reduction in the stimulating energy used according to the
Zacouto patent FR-A1-1,237,702, PV 651.632 of Jul. 11, 1953 and
allowing an instantaneous readjustment of the stimulating
parameters. One method of achieving this can consist in
progressively or abruptly reducing the stimulating pulse of the
pulse train until this pulse is recaptured. During the periods when
this pulse remains ineffective, the following pulse in its train
takes control of the heart. If a reduction in stimulating energy
remains sufficiently reliable, the OIST can be programmed to
trigger a stimulation, for example of reduced amplitude, and this
also reduces the risk of inducing extrasystoles. The amplitude
close to the threshold of the first three of four pulses in a train
comprising six or eight pulses can also be reduced, for example, by
one third, in order to observe whether or not this targeted
subliminal stimulation promotes the myocardial excitability
threshold. If this threshold turns out to be reduced, this
"facilitation" can be quantified, for example, as a percentage of
reducible amplitude, and its duration of facilitation can be
measured by a periodic repetition of this examination.
[0063] Conversely, a disruption in the stimulating pulse or the
complete stimulating train will trigger an instantaneous increase
in the energy amplitude of the pulse which has become subliminal or
of the entire stimulating train of the next cardiac cycle. In the
case of the following cardiac cycles, a pulse gradient with a
progressively increasing voltage can advantageously be used for
determining, by automatic measurement within each cardiac cycle,
for the inotropic orthorhythmic software program, the new
myocardial excitability threshold from which a new process for
control and intervention in the stimulating pulse amplitude will be
triggered.
[0064] Thus, the OIST performs optimum continuous instantaneous
adaptation of the stimulating intensities according to their
coupling intervals relative to the preceding wave R, whether it is
a spontaneous reduction or increase in the myocardial excitability
thresholds.
[0065] When attempting to specify a myocardial excitability
threshold, it is observed that it is not a spot limit but a zone
between the subliminal amplitude where there is no propagated
stimulation and the supraliminal amplitude where a constant
propagated drive element is observed. The extent of this inconstant
excitability zone is variable.
[0066] In a particularly preferred manner, the device comprises
means for giving a pulse intended for electrical stimulation an
amplitude greater than at least 30% and preferably between 30% and
90% of the amplitude of the last subliminal pulse observed.
[0067] The parameters on which the device acts can be merely a
programmed ventricular rhythm and/or an automatic adjustment of the
beginning or the end or the duration of the burst or the number or
the characteristics (in particular width, polarity, intensity) of
the pulses in the burst, or else a location of the transmission of
the burst over various stimulating electrodes. For example, a burst
can be reduced progressively to a single pulse. For this purpose,
it is possible to probe periodically with at least a second pulse
which moves progressively from, for example, 25 ms ahead of the
stimulating pulse and then retracts step by step, for example by 4
m/s during each cycle so as to automatically measure the beginning
of the non-refractory zone. When the exploratory pulse retracts
toward the stimulating pulse, this pulse itself is retracted until
the beginning of the reduction in the ventricular pressure/volume
curve or the increase in the oxygen consumption and/or the membrane
secretion and accumulation of electrons or, for example, proximal
catecholamines or lactic acid are obtained, this position
corresponding to the exceeding of the end of the mechanical
refractory zone with maximum active contraction known as MMRZ.
[0068] There are preferably provided means for anti-tachycardic
stimulation and means sensitive to the extrasystoles for
automatically stopping said stimulation if excessively great
hemodynamic instability or electrical arrhythmia corresponding to
predetermined criteria occurs.
[0069] The electrical stimulation of the heart according to the
invention allows the obtaining, during each cardiac cycle (CC), of
an optimum inotropic stimulation (OIST) which is paired (PST) or
coupled (CST) by very precise adjustments of the pulses relative to
the electrical refractory functional zones (ERZ) and myocardial
refractory functional zones (MRZ) and to the corresponding
metabolic reactions and in space relative to the cardiac locations
of the electrodes, allowing the best hemodynamics or
anti-arrhythmic efficacy to be obtained.
[0070] These functional zones can vary significantly during each
cycle, in particular in the case of myocardial disorders. In order
to control the ERZ and MRZ and the corresponding hemodynamics
during each cycle, these zones can be analyzed continuously and in
real time, for example using the means described in the Zacouto
patents, U.S. Pat. Nos. 4,052,991 and 3,857,399.
[0071] The device can comprise means for progressively reducing a
burst to a single pulse or a small number of pulses, in particular
by periodically probing with at least a second pulse which moves
progressively ahead of the stimulating pulse to automatically
measure the beginning of the non-refractory zone so that, when the
exploratory pulse retracts towards the stimulating pulse, the
stimulating pulse can be retarded, in particular periodically in
the event of instability in operation until the beginning of the
reduction of the ventricular pressure/volume curve or increase in
the oxygen consumption and/or a corresponding parameter, in
particular the membrane secretion of electrons, local pH or ketone
bodies is obtained, this position corresponding to the exceeding of
the end of the mechanical refractory zone with maximum contraction
(MMRZ).
[0072] It can comprise means for passing from paired stimulation to
coupled stimulation, in other words to a completely stimulated
rhythm, said means being sensitive to the means for acquisition of
the electrocardiogram and/or of the hemodynamics and/or of the
myocardial metabolism.
[0073] Instantaneous Inhibition of Extrasystoles or Arrhythmias
During OIST
[0074] The device according to the invention can also be arranged
to treat extrasystoles and arrhythmias which can appear either
spontaneously or due to the operation of the device.
[0075] Perfect operation of the OIST entails instantaneously
detecting the premature extrasystoles which can follow or accompany
a pulse train and also reacting instantaneously by inducing a
stimulation or a stimulation train from the beginning of detection
of such an extrasystole. The instantaneous detection of a premature
extrasystole necessitates an ECG recording that is preferably
independent of its intramyocardial directional propagation, which
is slow (1 m/sec), before arriving at the intracardiac detecting
electrode. Detection by juxta- or extra-cardiac or ventricular
intracavitary electrodes, preferably without contact with the
myocardium, which are sensitive to the speed of propagation of the
variations in the electrical field of the heart, which is close to
the speed of light, can be used for this purpose.
[0076] Once the detection of a premature extrasystole has been
confirmed, the anti-arrhythmic program will instantaneously trigger
a stimulation, preferably in a burst, from all the stimulating
electrodes available in order to induce as soon as possible a
fusion complex between the propagations of the stimulated and
extrasystolic depolarizations. This fusion complex will block the
propagation of extrasystolic depolarization and frequently allow
the suppression of premature myocardial ectopies. If premature
myocardial ectopies, in particular those which are repeated,
threaten the efficacy of the OIST, the diastoles can be
instantaneously and temporarily shrunk in order to close the
non-refractory intervals of the cardiac cycles during which the
triggering of the premature extrasystoles can occur.
[0077] In an embodiment of this type for the treatment of isolated
arrhythmias and extrasystoles, the device according to the
invention can comprise a plurality of electrodes disposed at
different locations of the heart muscle and/or at a distance from
the heart and acquisition means which are sensitive to the
electrical signals appearing at the electrodes and remotely from
them for observing, at an early stage, the occurrence of an
electrical extrasystole in a myocardial zone close to those of the
electrodes initially concerned. The stimulating pulse sending means
are thus made sensitive to such an observation so as to emit
instantaneously, in a nearby electrode or in a plurality of
electrodes, a stimulating pulse or burst of which the electrical
propagation into the myocardium is directed toward the myocardial
zone affected by the extrasystole and causing fusion between the
spontaneous and stimulated depolarizations which blocks the
propagation of the extrasystole.
[0078] In order to be able to detect sufficiently early and, in
particular, to be able to immediately send a stimulating pulse into
the vicinity of the territory currently affected by extrasystolic
depolarization, the device is preferably connected to a plurality
of electrodes such as electrodes in the region of the coronary
sinus, electrodes of the septum and the free ventricle walls and
preferably juxta-cardiac, extra-cardiac or intracavitary
electrodes, the device being arranged so that the acquisition means
detect the electrode close to the origin of the extrasystole, the
means for transmitting a stimulating pulse or a burst being
arranged so as to send the stimulation at least from an electrode
remote from the origin of the extrasystole.
[0079] Therefore, when the OIST is disturbed by untimely
occurrences of extrasystoles which are apparently self-induced, the
suppression thereof is promoted by an instantaneous electrical
response capable of occupying, at the earliest stage, the still
non-refractory zones of the myocardium. For this purpose, it is
preferable to detect the extrasystoles, not in the region of
bipolar intracardial catheters but in the extracardial region. In
fact, intracardial detection only "sees" the extrasystole coming
with a delay corresponding to its speed of propagation from its
creation until the arrival below the detecting electrode which
takes place at an intramyocardial speed of approximately 1
m/second. On the other hand, an electrode which is more external to
the heart "sees" the myocardial depolarization propagating at a
speed close to the speed of light. The extrasystoles, in particular
those considered dangerous by the programming, should therefore be
detected by means of juxta- or extra-cardial electrodes; as soon as
such a detection which is confirmed to be critical appears, a burst
of stimulations should be induced in the region of one or more or
preferably all of the stimulating electrodes. If there are a
plurality of stimulating electrodes, stimulation should be carried
out simultaneously from them so as to induce fused QRS complexes
which block the non-refractory myocardial spaces and thus prevent
propagation of new extrasystoles. This system should preferably act
within a single mechanical cardiac cycle.
[0080] The sequential recording of extrasystolic events, in
particular dangerous extrasystolic events, allows registers to be
created according to Zacouto's U.S. Pat. No. 5,306,293; this opens
up the possibility, in the event of crisis repetition, of carrying
out preventive stimulation, in particular temporary acceleration of
the basic rhythm before the reoccurrence of these
extrasystoles.
[0081] In a further embodiment, wherein the device comprises means
for rapidly detecting an extrasystole, the means of the device are
sensitive to the acquisition of this extrasystole for reducing or
even suppressing, preferably temporarily, the electrical diastolic
phases (D). This is effected either by increasing the stimulation
rhythm in a heart under electrical control of the device or by
taking the control to send a stimulating pulse at the very
beginning of the electrical diastole.
[0082] In these latter cases, the device according to the invention
passes from the state of paired stimulation to the state of coupled
stimulation.
[0083] The installation of tachycardia can thus be prevented while
maintaining a rhythm well below the first tachycardiac rhythm and
while benefiting from a post-extrasystolic potentiation effect.
[0084] A device of this type is particularly effective in
controlling nascent arrhythmias induced by stimulation or
originating close to the zone or zones into which the stimulating
pulses or bursts are sent.
[0085] In a further embodiment, the number and/or intensity of
pulses of the burst can be temporarily increased on appearance of
an arrhythmia in order to potentiate the effect of stabilization on
the myocardial cell membranes or automatically administer, by an
OIST program, a drug which perfuses or comes from an implanted
medicament reservoir (see, in particular, Zacouto, U.S. Pat. No.
5,305,745).
[0086] In other cases, the device can be arranged so as, on the
other hand, to reduce the intensity of the pulses of the burst in
the event of arrhythmia, the device then monitoring whether
arrhythmia continues. In this case, the intensity of stimulation
could be increased.
[0087] In a further embodiment, the device according to the
invention can be effectively used in the event of auricular
fibrillation, leading to ventricular arrhythmia. The device
according to the invention is arranged so as to acquire the cardiac
mechanogram, preferably until the occurrence of a cycle which is
sufficiently long to obtain a good myocardial contraction relative
to the current instantaneous rhythm defined, for example, by a
preprogrammed threshold and the stimulating means then transmit a
stimulating pulse or burst at an instant within the systolic
plateau of the mechanogram curve, in other words from the
relatively flattened peak of the mechanogram curve.
[0088] Once the device has acquired an immediately preceding cycle,
the electrical refractory period ERZ can be situated as a
percentage of the duration of the preceding cycle, the pulse being
launched into said plateau of the hemodynamic curve preferably just
before the end of this contracted maximum mechanical refractory
zone, for example 30 to 40 ms before the end of this zone MMRZ,
this zone end being detectable by an intramyocardial local pressure
microsensor at the point close to the active electrode for
transmitting a burst of pulses spaced by 15 ms, after which the
device immediately stimulates, preferably in a multipolar manner,
after the end of the electrical refractory zone which has just been
extended, thus canceling the electrical diastole. Advantageously,
this can be carried out on electrodes located in the vicinity of
the zone which saw the arrhythmia appear by using electrodes
disposed in the above-described manner.
[0089] For example, the device can firstly stimulate the atrium
with an intra-auricular electrode then, if necessary, the ventricle
with an intra-ventricular electrode, in a succession which is well
known in pacemakers of the DDD type. The auricular myocardial
tissue can thus be regenerated or improved by OIST stimulation in
the auricular region.
[0090] In a further embodiment, when the patient's His bundle is
more or less blocked, for example by Digoxin, the frequency of
stimulation can be progressively reduced while monitoring premature
contractions of auricular origin.
[0091] The device according to the invention can be integrated in
an automatic defibrillator (IAD), for example an implanted
defibrillator, and can be used, in particular after a
defibrillation shock, or else to prevent grave arrhythmias.
[0092] The implanted defibrillators currently comprise
anti-tachycardic means of the anti-arrhythmic type according to
Zacouto's U.S. Pat. No. 3,857,399, and the device according to the
invention can, for example, be actuated when the anti-tachycardic
device does not manage to rapidly reduce a tachycardia.
[0093] Inotropic Stimulation During the Muscular Refractory Zone of
Maximum Contraction (MMRZ)
[0094] In a preferred method of optimization, the software
controlling the device according to the invention is programmed so
as to automatically find the narrow effective zone MMRZ in each
cycle concerned and optionally to then reduce the various
parameters of the pulse bursts, in particular the number pulse
bursts, so as to end up, if possible, with a single perfectly
targeted pulse. Since such stability in operation of the OIST is
non-existent or inconstant, particularly in the case of myocardial
suffering, the programming which continuously detects the
mechanical parameters, preferably with the metabolic (oxygen or
equivalent) consumption thereof, should reverse the burst reduction
process (in the event of adequate or increasing instability), so as
to find the location of the new useful narrow zone of the cycle
without delay with the bursts. A fast method for finding the zone
MMRZ involves detecting, within a burst, the effective pulse which
produces propagated depolarization and progressively reducing its
distance from the preceding pulse until it is disrupted and no
longer leads to visible electrogenesis on the electrocardiogram
which will be induced, at this moment, by the following pulse of
the burst. The beginning of the useful zone is thus known precisely
and it is possible to add approximately 20 ms and to consider that
this interval represents the useful zone at a given period. This
automatic research, which is harmless to the patient, should be
repeated periodically so as not to lose the exact location of the
MMRZ during the variations thereof. After the effective pulse of
the pulse burst has been found, the voltage or the width of the
other pulses can be reduced so as to render them slightly
subliminal, and this can maintain their anti-arrhythmic effect as a
functional sentinel, because a subliminal pulse close to the
threshold often influences this threshold by reducing it for a
short period (facilitation effect). This phenomenon can be measured
automatically while slightly reducing the intensity of the pulse or
pulses preceding the stimulating pulse in a burst and while
progressively reducing the intensity, the voltage or the width of
the stimulating pulse until its functional disruption, the
following pulse of the burst maintaining a stimulating intensity;
the intensity of this pulse can then also be reduced progressively
so that the variation in its excitability threshold can be measured
and, by shifting it progressively over time, the duration and
intensity of this facilitation effect can thus be measured.
[0095] In a variation, for detecting the maximum contraction zone
MMRZ, the device can comprise means for the precise measurement of
the volume of the heart or of a part of the heart by electrical
impedance or else by localized echography, for example in that it
comprises a tissue-measuring echographic ultrasonic probe which is
oriented toward a heart wall in order to measure the displacement
thereof, thus allowing the variations of the myocardial volume to
be obtained in real time and the moment of the maximum contraction
thus to be determined.
[0096] The invention accordingly relates to a device for
stimulating and/or potentiating the heart muscle and/or the
myocardial cells, for significantly increasing the hemodynamic
performance of the heart and/or the treatment of auricular
tachycardia, tachyarrhythmia or fibrillation comprising:
[0097] means for the precise acquisition of the cardiac
hemodynamics (5, 6) and comprising a means for instantaneous
detection of the maximum myocardial refractory zone (MMRZ) at a
precise location of the myocardium,
[0098] and means for sending at least one stimulating pulse and
preferably a burst of stimulating pulses from the local region in
which the occurrence of the zone MMRZ is detected.
[0099] It preferably comprises means for automatic acquisition (1,
2, 3) of the heart rhythm and optionally of its origin, in
particular for obtaining the interval between at least the last two
waves R (induced or spontaneous) of the cardiac cycle which has
just been completed and means (4) for determining continually in
real time the duration of the electrical refractory period (ERZ)
following the last wave R of a cardiac cycle, said device being
arranged so as to detect whether an electrical depolarization
signal has been produced by said stimulation in said zone MMRZ.
[0100] These means allow the detection and storage of the duration
of said maximum myocardial refractory zone (MMRZ) and the sending
of said local stimulating pulse or burst of stimulating pulses
after a short duration after the beginning, in the current cycle,
of the beginning of said zone MMRZ and before the estimated end of
said zone by storing said duration in the preceding cycles.
[0101] According to the invention, the stimulating pulse or at
least one stimulating pulse of a burst falls in said zone (MMRZ),
substantially at the location of the myocardium where the
occurrence of said zone (MMRZ) is detected.
[0102] The device can comprise implanted means for measuring
intracavitary pressure and capable of detecting a zone of maximum
pressure in the plateau of the cardiac mechanogram and to which
said means of transmitting a stimulating pulse or burst are
sensitive.
[0103] Preferably, it comprises at least one sensor for detecting
intramyocardial pressure. Said intramyocardial pressure sensor is
situated in the intra-auricular septum and/or in a free cardiac or
intra-ventricular wall.
[0104] In a variation there can be provided means for measuring the
variation in the volume of the heart or a part of the heart,
detecting and storing the interval of the cycle where said volume
has reached and maintained its minimum value, said means for
sending a stimulating pulse or burst being sensitive to said
measuring means.
[0105] There can thus be provided means for detecting the oxygen
consumption of the heart and/or an equivalent, in particular the
local pH or concentration of ketone bodies, and means for detecting
the zone of maximum cardiac contraction (MMRZ) by estimation by
detecting, during one or more previous cycles, the relative
position in the cycle and/or in the mechanogram of the pulse or of
the pulse of a burst which has generated post-extrasystolic
potentiation (PESP) with minimal oxygen consumption relative to the
measured blood flow per minute.
[0106] Comparative Analysis with Simulation
[0107] A safety OIST at clinical level necessitates effective
methods of protection against interfering extrasystoles and
spontaneous variations in the refractory zones of the myocardium
which can be increased by the actual stimulation in bursts.
[0108] The size and speed of the variations in the electrical and
mechanical refractory zones of the heart can be explained by the
additional energetical force which the OIST demands during each
myocardial contraction. The organism tends to avoid this force,
which is imposed by very precise targeting of the pulses in each
cardiac cycle, by modifying both the durations and the excitability
thresholds of these zones. However, mere adaptation, even if
perfect, to the various myocardial parameters is not always
sufficient to detect the blood flow of each contraction, because
the variations in the intrinsic parameters (intracellular
electromechanical coupling) of the contractile apparatus remain
unknown. It follows that precise, constant and comparative analysis
by a "simulator" of the actual blood flow, in real time, relative
to the preceding cycles with monitoring and possibility of
automatic intervention in the OIST remains necessary.
[0109] It should be borne in mind that, in the event of grave or
acute cardiac failure, the continuous maintenance of an OIST
becomes more difficult, and it should be possible to anticipate the
development, particularly in the short term, of the critical
cardiac parameters. For this purpose, the variations in parameters
which previously induced an unjustified risk of disruption of the
OIST are stored and stimulation is carried out in an attempt to
avoid similar concordances; in the event of justified disruption,
for example arrhythmia or critical, purely myocardial failure, the
OIST will be programmed to stop instantaneously with emission of an
alarm and analysis of the responsible cardiac parameters and, if
necessary, defibrillation or anti-tachycardic stimulation or
automatic injection of drugs. These safety functions can be
performed by an analyzing simulator (ASIM) employing, in
particular, the comparative analysis between, on the one hand, the
simulated ECG and hemodynamic and/or metabolic curves relative to
patient data and, on the other hand, actual curves recorded in real
time and superimposed.
[0110] The invention of the OIST, by adapting without delay to
these different variations in spontaneous functional spacing of the
heart, provides continuity of its optimum inotropic effect.
[0111] Analysis by theoretical simulation adapted to each patient
and its difference from the actual curve of the cardiac and
vascular parameters in real and deferred time allows the functional
reactivity of the myocardium toward its stimulation by the
inotropic orthorhythmic pacemaker to be shown continually. This
OIST stimulation allows the differences between the desired curves
and the actual curves as well as the variations thereof to be
displayed instantaneously and magnified as desired, and this in
turn allows the electrical stimulation parameters to be readjusted,
if necessary, instantaneously and automatically. It is thus
possible to hatch, color differently and continually quantify
automatically the differences in subtraction of these curves. A
manual readjustment cannot be as fast and quite frequently
necessitates the prior understanding of the physiopathological
mechanism concerned.
[0112] In view of the available information on a patient's heart
and the functioning thereof, a simulation of the effects, which are
theoretically legitimately expected, can thus be established by
carrying out the process according to the invention, and this
simulation and the actually effected stimulation can be
compared.
[0113] In this embodiment, the device comprises:
[0114] means for acquiring information relating to a patient's
electrocardiogram, including the heart rhythm,
[0115] means for acquiring information relating to the patient's
hemodynamic performance,
[0116] analysis means which are sensitive to said acquisition means
for simulating the effect of an inotropic paired or coupled
stimulation adapted to the patient's heart.
[0117] It advantageously also comprises means for automatically
comparing said acquired information on the patient's hemodynamic
performance with the simulated effect on said performance of
inotropic paired stimulation.
[0118] Preferably, said acquisition and comparison means allow the
acquisition and comparison of information cycle by cycle.
[0119] The parameters for determining the state of a patient's
heart and its reactivity include its electrocardiogram in the
spontaneous state or with the assistance of a pacemaker, for
example an orthorhythmic pacemaker. They also include information
about the hemodynamic performance of the muscle and its reactivity
to electrical stimulations. The various parameters and means for
acquiring them and, in particular, for cardiac efficacy, including
flow, volume and pressure, oxygen consumption etc. have been
defined hereinbefore and are also described in the documents
incorporated by reference thereto.
[0120] Preferably, said parameters include at least one of the
following parameters relating to the contraction:
[0121] gradient (dp/dt) of the phases of ascent and/or descent of
the intracavitary and/or intramyocardial pressure;
[0122] duration of the systolic pressure plateau, corresponding to
systolic ejection;
[0123] duration of the systole (cardiac contraction);
[0124] duration of the diastole (fast and slow active motor filling
phases);
[0125] ratio between the diastole and systole durations;
[0126] quality of the diastole, in particular filling
depression;
[0127] electromechanical coupling (period separating the beginning
of a QRS complex from the beginning of the mechanical systole which
it causes).
[0128] Preferably, the device comprises means for comparing
information about the electrocardiogram and the hemodynamic
performance of a simulation of inotropic paired or coupled
stimulation with corresponding information acquired during an
subsequent identical or similar actual inotropic stimulation.
[0129] Preferably, it comprises means for acquiring or calculating
a threshold level for values of the information on the simulated
hemodynamic performance adapted to the patient and, if the
threshold is exceeded, causing an identical or similar inotropic
paired or coupled actual stimulation.
[0130] Said means for acquiring information relating to the
patient's electrocardiogram and to the patient's hemodynamic
performance are arranged so as to acquire this information at
different rhythms.
[0131] Preferably, the device is arranged so as to temporarily
impose, on the patient's heart, rhythms which vary in increments or
progressively, during which said information relating to the
electrocardiogram and said information relating to the
corresponding hemodynamic performance are acquired.
[0132] Preferably, said means sensitive to the acquisition means
are arranged so as to simulate the effect of a plurality of
inotropic paired or coupled stimulations at different heart
rhythms.
[0133] Preferably, said comparison is carried out for a limited
number of cycles of actual inotropic stimulation and, if the
absence of a satisfactory level of hemodynamic performance is
observed, the current stimulation is terminated.
[0134] Said number of cycles may be approximately 10 or less, in
particular 1, 2 or 3 cycles.
[0135] Preferably, the device is arranged so as, if an adequate
increase in initial hemodynamic performance is observed, to
continue the inotropic stimulation and to detect and store whether
the increase in initial hemodynamic performance is maintained
and/or further increases progressively for a greater number of
cycles.
[0136] Said greater number of cycles is preferably at least about
100 cycles.
[0137] Said means are arranged so as to include the medicinal
inotropic effects likely to interfere with the effect of electrical
inotropic stimulation.
[0138] The device can comprise means for emphasizing, visually
and/or quantitatively by calculation, the differences between the
curves for the stimulation and for the corresponding actual
stimulation.
[0139] Preferably, all this information relating to the
electrocardiogram, the heart rhythm and the hemodynamic or
physiological characteristics is obtained and stored in the device
according to the invention, whatever the patient's spontaneous or
stimulated heart rhythm. In such a case, the simulation is refined
by the analysis made by comparing the variations in the parameters
and in particular in the above-listed parameters, at the various
rhythms.
[0140] These changes in cardiac rhythm or reactivity can also be
acquired by subjecting the patient to appropriate medicaments which
act, for example, on the heart rhythm and/or the cardiac
contraction, for example Dopamine.
[0141] Thus, for example, the electromechanical coupling and the
manner in which it can vary when the rhythm varies will give a good
indication of the mechanical reactivity of the heart after
stimulation. The gradient of the rise in pressure (dp/dt) will give
an indication of the capacity of the heart muscle to create a rise
in pressure, whereas the gradient of the drop in pressure could be
indicative of the compliance or elasticity of the heart muscle and
therefore of its capacity to fill during the mechanical diastole,
according to the rhythm.
[0142] The device according to the invention is programmed to use
the information thus acquired and propose, at least for the
patient's spontaneous rhythm or base rhythm, and preferably for
other rhythms, an electrocardiogram and a mechanogram simulating a
result of functioning with paired or coupled stimulation according
to the invention.
[0143] A simulated mechanogram thus allows, in particular, the
simulated cardiac output to be obtained, and this simulated rate
can then be compared with the measured rate of the patient
[0144] in a spontaneous rhythm or in a simulated base rhythm if
necessary, and it can be estimated whether the implementation of
inotropic stimulation according to the invention would lead to a
significant increase, preferably of at least 20%, in the output,
leading to a significant improvement in the patient suffering from
heart failure. The production of simulations at different rhythms
allows cardiac outputs corresponding to these respective rhythms to
be estimated and, if necessary, a particular rhythm, in particular
an accelerated rhythm, to be selected for a patient suffering from
cardiac failure and having a relatively low spontaneous rhythm, or
a reduced rhythm for example in the case of a patient having a high
spontaneous rhythm which it is hoped to reduce by the inotropic
stimulation according to the invention.
[0145] The following stages of the process according to the
invention therefore involve applying the selected inotropic
stimulation to the patient by means of the simulation step,
instantaneously acquiring the results of this stimulation and
comparing these results with the theoretical simulated results.
[0146] The device is preferably programmed so as to immediately
check the changes in hemodynamic performance after a very small
number of cardiac cycles, for example, during one, two or three
mechanical cycles or during one or a few tens of cycles. If a
significant improvement fails to appear or to be maintained, for
example after three cycles, the device stops inotropic stimulation
or, depending on the programming provided, attempts inotropic
stimulation under different conditions, for example at a different
rhythm.
[0147] If an initial actual improvement in hemodynamic performance
is observed after this small number of cycles, the inotropic
stimulation according to the invention is continued for at least
about one hundred or a few hundred cycles, and the device checks
whether the increase in initial hemodynamic performance occurring
at the very beginning of inotropic stimulation is not only
continuous but also progressively increases during this greater
number of cycles and will be stored.
[0148] The comparison between the simulated increase in hemodynamic
performance and the actual increase or change in hemodynamic
performance can be obtained, for example, by superimposing the
simulated and actual hemodynamic curves and measuring the
differences, namely at least the difference in flow, and preferably
differences from other parameters, in particular specific
parameters or all of the parameters listed above.
[0149] It could be decided, for example, if the difference, in
particular with regard to flow, is negative and is below a
threshold, for example 10 or 20% below the simulated flow value,
that the inotropic stimulation which has been carried out is not
sufficient, the device thus stopping isotropic stimulation or
attempting other inotropic stimulation.
[0150] On the other hand, if the increase in hemodynamic
performance exceeds the simulated increase by a value, for example,
of at least 10 or 20%, control of inotropic stimulation, for
example by transmission of paired or coupled stimulating pulses or
bursts only for specific cardiac cycles and not during each cycle,
could be considered and the oxygen consumption indices or other
indices such as those defined in the earlier documents incorporated
by reference, could also be used to check that the increase in
hemodynamic performance is not taking place to the detriment of the
availability of oxygen for the patient.
[0151] In addition, with the improvement according to the
invention, the electrical and mechanical results of inotropic
stimulation according to the invention will be recorded and
processed with those previously acquired for carrying out
simulation in order to specify better the particular
characteristics of the patient's heart as defined, for example, by
the various aforementioned parameters, and this will then allow
electrocardiograms and/or electromechanical curves of simulation to
be obtained.
[0152] Particularly if OIST is applied to patients suffering from
grave or acute heart failure, it is found that it may be impossible
to start OIST or OIST is disrupted during operation. In order to
anticipate and prevent these grave incidents, the cause of
malfunctioning of OIST should be carefully analyzed. It is
frequently due to inadequate superimposition of the electrical
refractory zones (ERZ) and mechanical refractory zones (MMRZ) which
can be shrunk or moved relative to one another in such a way that
the duration of the effective critical zone (ECZ) is virtually
cancelled or, more frequently, reduced, for example to 10 ms. In
this case, if the stimulating burst of the OIST consists of pulses
with an interval of 15 ms, it becomes impossible to carry out
continuous inotropic stimulation and the patient's oxygen reserves
are likely to be exhausted.
[0153] According to a variation of the invention and in order to
avoid this grave failure of the OIST, the time durations and
superimpositions of these ERZ and MMRZ should be measured precisely
substantially in the same location of the heart and, if necessary,
continuously; this function can be performed by the analyzing
simulator (ASIM). When the ASIM records a critical shrinkage of the
ECZ, it can suitably bring together the pulses of the bursts
automatically without delay in an attempt to cause at least one
pulse to target regularly within the ECZ. If it is impossible to
reach the ECZ regularly, the ASIM is programmed to stop the OIST
without delay. A continuous bringing together of the pulses to
within 10 ms prevents ERZ measurement, in the current state of
electronics, and includes other electronic and possibly
physiological drawbacks.
[0154] Preferably, the device comprises:
[0155] means for continuously measuring electrical refractory zones
ERZ in a location of the heart,
[0156] means disposed substantially in the region of the heart for
precisely measuring the zones of maximum myocardial contraction
MMRZ,
[0157] the device being arranged so as to acquire, from said means,
the temporal superimposition, in the same cycle, of said zones ERZ
and MMRZ and determine the common zone known as the critical zone
ECZ.
[0158] The electrical stimulating means are arranged so as to
immediately send at least one stimulating pulse into said region of
the heart during said zone ECZ.
[0159] As an improvement said means for checking the temporal
superimposition are sensitive to a shift between the zones ERC and
MMRZ in order to send a stimulating pulse or a burst supplying at
least one pulse to the interior of the zone ECZ.
[0160] Preferably, said sensitive means enable the time interval
between two pulses of a burst to be reduced so as to increase the
probability of having a pulse during said zone ECZ.
[0161] Preferably, the duration between two pulses of a burst
cannot be reduced to less than a value of approximately 10 ms.
[0162] Preferably, if it is impossible to cause at least one pulse
to travel to the interior of the zone ECZ, the device stops the
coupled or paired stimulation.
[0163] According to an improvement, the device stores the
occurrences and time durations of the zones ECZ during a plurality
of cycles and the development thereof is analyzed in order to
anticipate any tendency to the suppression of said zone ECZ and, in
this case, to implement a treatment, in particular by perfusion of
drugs or change of the OIST rhythm in order to act on the duration
of the zones ERZ or MMRZ or the overlap thereof.
[0164] The means used by the device according to the invention,
unless otherwise described, are means which, in their
individuality, are conventional in the art and described, for
example, in the various documents incorporated by reference.
[0165] Thus, the acquisition means combine electrodes, known
physical or biochemical sensors with signal shaping means and data
processing means, including microprocessors and memories, with
software which is known to a person skilled in the art or which he
can produce in a routine manner once he has read about the
operation described by the invention. The same applies to the means
used for stimulation, including their electric power source, and
the data processing means which are sensitive, for example, to the
rhythms, durations, detection thresholds and electrical or
hemodynamic or biochemical curves acquired or produced.
[0166] The invention also relates to processes for treating or
preventing cardiac diseases comprising the successions of steps
described hereinbefore, these processes employing a device as
described in the present invention.
[0167] In a first practical example, therefore, the invention
relates to a process for electrical stimulation of the heart, in
particular for treating or preventing cardiac failure and, in
particular left ventricular failure or tachycardia, arrhythmia or
else for significantly increasing hemodynamic performance of the
heart, said process comprising the following steps:
[0168] implanting a stimulating device as described according to
the present invention;
[0169] automatically acquiring information on the heart rhythm,
preferably by acquiring the electrocardiogram, preferably with
accelerated development;
[0170] determining, preferably during each cycle, preferably in
real time, the duration of the electrical refractory period (ERZ)
following the last wave R of the current cycle or of another nearby
earlier cycle;
[0171] and, during the following cycle, sending, substantially
without delay before the end of said determined refractory period
(ERZ), at least a stimulating pulse, preferably a burst of
stimulating pulses, so as to induce a significant extension of the
refractory period (ZR) without causing any mechanical stress.
[0172] In a second embodiment, a process according to the invention
for stimulating the cardiac muscle, in particular in the case of
one of the aforementioned diseases, comprises the following
steps:
[0173] automatically acquiring information on the heart rhythm,
preferably by acquiring the electrocardiogram;
[0174] determining, preferably during each cycle, preferably in
real time, the duration of the electrical refractory period (ERZ)
following the last wave R of the current cycle or another formerly
nearby cycle;
[0175] sending, during the following cycle, substantially without
delay at the end of said determined refractory period (ERZ) at
least one stimulating pulse, preferably a stimulating burst;
[0176] automatically acquiring information on the cardiac
hemodynamics, preferably the pressure/volume curve of the cardiac
contraction;
[0177] determining the potentiation of said hemodynamics;
[0178] in the case of zero or excessively weak potentiation,
modifying the moment of sending and/or the parameters of said pulse
or burst until a higher degree of hemodynamic performance is
obtained.
[0179] In a particularly preferred embodiment, means (4) for
determining the duration of the electrical refractory period (ERZ),
which are sensitive to the detection of the pulse in a burst which
triggered a complex R', and means for determining the maximum
mechanical refractory zone MMRZ are used, and a zone ECZ posterior
to the electrical refractory zone ECZ [sic] is determined in said
zone MMRZ and, if said zone ECZ exists, at least one stimulating
pulse is sent into said zone ECZ.
[0180] In a particular embodiment of said processes of the
invention, the heart is allowed to generate the spontaneous
electrical systole R which induces the contractions of the cardiac
muscle. The sending of the pulse or the burst or trains of pulses
just before the end of said refractory period can thus be said to
be "paired" with said spontaneous electrical systole R.
[0181] In a further embodiment, which can thus be used optionally
together with the preceding embodiment and in particular in the
case of bradycardia or else for the orthorhythmic reduction of
tachycardia, a stimulating pulse is regularly sent to the heart to
induce a stimulated electrosystole R which leads to myocardial
contraction and the coupling pulse or the stimulating burst
according to the invention is sent substantially without delay at
the end of the refractory period, the heart thus being stimulated
at an electrical rhythm, said stimulating pulse or burst thus being
said to be "coupled" to the electrosystole.
[0182] In the processes according to the invention, the duration of
the electrical refractory period (ERZ) can be determined by stages
such as those described with regard to the operation of the device
according to the invention, for example by calculation and/or
scanning and/or measurement.
[0183] In a particular embodiment of the processes according to the
invention, wherein a burst of pulses is sent, the burst of pulses
is sent just before the estimated end of the refractory period ERZ,
the duration of the burst and the number of pulses being such that
an electrical stimulation occurs very quickly after the end of said
refractory period (ERZ).
[0184] In a perfected embodiment, that pulse of the burst which
triggered a wave (R') extending the refractory duration (ERZ) is
detected and, if necessary, at least one characteristic of the
burst is modified during the following cycle.
[0185] These characteristics include, in particular, the instant
when the burst began, its duration, the number of pulses, the pulse
interval and the intensity of the pulses of the burst.
[0186] Preferably, anti-tachycardic stimulation means and
extrasystole-sensitive means are also used for automatically
stopping said stimulation on the occurrence of excessively great
hemodynamic instability and electrical arrhythmia corresponding to
preselected criteria.
[0187] In addition to the rhythm acquisition means, means for
determining the duration of refractory zone and means for
transmitting a pulse or a burst, there can be used means (7, 10)
which are sensitive to the precise acquisition of the hemodynamics
for determining the variations in efficacy of the hemodynamics,
these means being capable of controlling the transmission and
optionally the parameters of the pulse or the burst, preferably in
a manner resembling that which produced the hemodynamics which are
most favorable for the patient at a given moment.
[0188] Said means act on parameters such as: a programmed
ventricular rhythm and/or an automatic adjustment of the beginning
or end or duration of the burst or the number or the
characteristics, in particular width, intensity, polarity, density,
interval of the pulses in the burst, or else a location of the
transmission of the burst at one or more stimulating
electrodes.
[0189] Preferably, metabolic parameters, in particular of oxygen
consumption and/or the equivalents thereof such as the measurement
of electron densities of myocardial cell membrane or increase in
ketone bodies, lactic acid, etc. are acquired.
[0190] In a perfected embodiment of the process, a stimulating
pulse or burst is sent into the zone (MMRZ) situated within the
plateau of the contraction curve of the mechanogram and during
which the contraction of the myocardium is substantially at its
peak.
[0191] Thus, the stimulating pulse or at least a stimulating pulse
of a burst falls within said zone MMRZ. Preferably, said zone
(MMRZ) is acquired automatically.
[0192] In an embodiment, the intracavitary pressure is measured by
a sensor and a zone of maximum pressure is selected in the systolic
plateau of the cardiac mechanogram in which the transmission of a
stimulating pulse or burst is induced.
[0193] Preferably, however, the local intramyocardial pressure is
measured in the vicinity of a detecting and stimulating
electrode.
[0194] Preferably, the myocardial pressure is detected in the
intra-auricular and/or intraventricular septum.
[0195] In a further embodiment, the variation in the volume of the
heart or a part of the heart is measured by detecting the zone
where said volume has reached and maintains its minimum value.
[0196] The invention also relates to a process wherein:
[0197] information to relating to a patient's electrocardiogram,
including the heart rhythm, is acquired,
[0198] information relating to the patient's hemodynamic
performance is acquired;
[0199] and this information is used to simulate the effect of
prolonged inotropic paired or coupled stimulation.
[0200] Said acquired information relating to the patient's
hemodynamic performance is compared to the simulated effect on said
performance of an inotropic paired stimulation.
[0201] Preferably, the information is acquired and compared cycle
by cycle.
[0202] Preferably, at least one of the following parameters
relating to cardiac contraction is measured:
[0203] gradient (dp/dt) of the phases of ascent and/or descent of
the intracavitary and/or intramyocardial pressure;
[0204] duration of the systolic pressure plateau, corresponding to
systolic ejection;
[0205] duration of the systole (cardiac contraction);
[0206] duration of the diastole (filling phase);
[0207] ratio between the diastole and systole durations;
[0208] quality of the diastole, in particular filling depression or
speed and amplitude of the fast and slow phases;
[0209] electromechanical coupling (period separating the beginning
of a QRS complex from beginning of the mechanical systole which it
causes);
[0210] shift between the local intramyocardial contraction curve
close to the local detecting electrode and the global intracavitary
contraction curve.
[0211] Information relating to the electrocardiogram and to the
hemodynamic performance of a simulation of inotropic paired or
coupled stimulation is compared with corresponding information
acquired during a subsequent identical or similar actual inotropic
stimulation.
[0212] Preferably, a threshold level for values of the information
on the simulated hemodynamic performance of the patient is acquired
or calculated and, if the threshold is exceeded, an identical or
similar inotropic paired or coupled actual stimulation is
triggered.
[0213] Preferably, the information relating to the patient's
electrocardiogram and to the patient's hemodynamic performance is
acquired at different rhythms, in particular rhythms which increase
or decrease by increments or progressively.
[0214] Preferably, there are used means which are sensitive to said
acquisition means arranged so as to simulate the effects of a
plurality of inotropic paired or coupled stimulations at different
heart rhythms.
[0215] Preferably, said comparison is effected for a limited number
of cycles of the actual inotropic stimulation and, if the absence
of a satisfactory hemodynamic performance level is observed, the
current inotropic stimulation is terminated.
[0216] If an adequate initial increase in hemodynamic performance
is observed, inotropic stimulation is continued and it is detected
whether the initial increase in hemodynamic performance is
maintained and/or still increases progressively for a greater
number of cycles.
[0217] The effects of cardiovascular target medicaments, which have
previously been administered or are being administered, are used in
the analysis.
[0218] Preferably, the differences between the simulation and
stimulation curves are emphasized visually and/or quantitatively,
in particular by superimposition of the curves.
[0219] Preferably, the cardiac mechanogram is acquired, in
particular until the appearance of a cycle which is long enough to
obtain a good myocardial contraction, and a stimulating pulse or
burst is then transmitted at an instant within the plateau of the
mechanogram curve (MMRZ), in particular just before the end of the
electrical refractory zone (ERZ), after which stimulation is
carried out immediately after the end of the electrical refractory
zone which will cause a new electrical refractory zone.
[0220] Advantageously, a first threshold of increase in global
hemodynamic performance/mn and/or per cardiac contraction can be
defined, in particular the cardiac output, said threshold being
equal to at least 15% or preferably 25% of the performance prior to
treatment, and the stimulation parameters are adjusted until at
least said threshold value is obtained.
[0221] If the increase according to said first threshold value is
not obtained during a period of approximately 1 to 10 contractions,
it is preferable to stop the treatment.
[0222] The invention also relates to a process for treating acute
or severe heart failure wherein:
[0223] the heart rhythm and, in particular, the interval between at
least the last two waves R (induced or spontaneous) of a cardiac
cycle which has just been completed are automatically acquired,
[0224] the duration of the electrical refractory period (ERZ)
following the last wave R of said cycle is determined, preferably
continually,
[0225] at least one stimulating pulse and preferably a stimulating
pulse burst is sent substantially without delay at the end of the
refractory period (ERZ), the duration of the burst being such that,
in view of the pulse repetition interval in the burst, a
stimulating pulse of the burst is sent to the heart substantially
without delay after the end of the refractory period, and
[0226] these steps are repeated for a series of at least three
contractions if an initial improvement in cardiac performance is
observed, and
[0227] and, in the absence of an improvement, the process is
automatically stopped.
[0228] Advantageously, the total mechanical performance of the
heart, in particular its blood flow and/or the variation in
ventricular volume are compared, on the one hand, before carrying
out the steps of the process and, on the other hand, after carrying
out the steps of the process and, if the increase in heart
performance is greater than 15%, the steps of the process are
carried out again.
[0229] The invention also relates to a process for cardiac
resuscitation in a patient suffering from severe or critical heart
failure wherein:
[0230] the heart rhythm and, in particular, the interval between at
least the last two waves R (induced or spontaneous) of a cardiac
cycle which has just been completed is automatically acquired,
[0231] the duration of the electrical refractory period (ERZ)
following the last wave R of said cycle is determined, preferably
continually,
[0232] at least one stimulating pulse and preferably a stimulating
pulse burst is sent substantially without delay at the end of the
refractory period (ERZ), the duration of the burst being such that,
in view of the pulse repetition interval in the burst, a
stimulating pulse of the burst is sent to the heart substantially
without delay after the end of the refractory period, and
[0233] these steps are repeated at least until an at least
progressive improvement in detectable cardiac performance is
achieved.
[0234] The treatment and resuscitation processes can advantageously
also employ the other steps of the processes described
hereinbefore.
[0235] The invention also relates to processes for the treatment or
prevention of cardiac arrhythmia, in particular spontaneous cardiac
arrhythmia, employing the steps enumerated hereinbefore for
application of the device for preventing arrhythmia. It also
relates to processes for treating or preventing cardiac arrhythmia
caused by or associated with the use of a device according to the
invention, said process employing the corresponding steps
enumerated herein before.
[0236] Regeneration of the Myocardium
[0237] The invention also relates to a process for physiological
and/or anatomical and, in particular, cellular regeneration of the
myocardium in the case of heart muscle failure, this process
preferably comprising the steps described herein before.
[0238] A process of this type according to the invention comprises
the following steps:
[0239] implanting in the heart, in particular in a right or left
atrium and/or a right or left ventricle, regeneration cells, in the
sub-endocardial or intramyocardial position, preferably in a
plurality of groups of cells or in a cell blanket or cell mesh,
[0240] and carrying out stimulation according to the invention,
preferably paired stimulation.
[0241] A process of this type according to the invention comprises
the following steps:
[0242] obtaining and cultivating, in vitro, regeneration cells,
preferably in the form of small groups;
[0243] placing the confluent cells in electrically conductive
contact with one another and with an electrical stimulation
device,
[0244] periodically sending electrical pulses to said cultivated
cells;
[0245] detecting the electrical responses of the depolarizations
and repolarizations or membrane potentials of the cultivated cells,
said cells being intended to be implanted in the heart, preferably
in a plurality of groups or sheets of cells, in a sub-endocardial
or intramyocardial position, once the electrical detection thereof
by intracellular microelectrodes has demonstrated the cell capacity
for rhythmic electromechanical activity adapted to the recipient's
myocardium.
[0246] The stimulation can be a mere electrical stimulation having
a rhythm which preferably resembles the normal heart rhythm. It
can, preferably after an initial period, be sent in a paired or
coupled form, once the groups of cells in culture are synchronized
and manifest an acceptable electrical refractory period relative to
the recipient's myocardium.
[0247] The cultivated cells may be of any type, for example muscle,
myocardial, embryonic cells or stem or totipotent or multipotent
cells.
[0248] These cells may also have been obtained by a process wherein
a nucleus or a part of nuclei or of foreign chromosomes or genes
are transferred into a functional oocyte or a totipotent or
multipotent or embryonic stem cell and this nuclear material is
removed at an incomplete stage of mitosis for transfer into a
totally or relatively differentiated, preferably original or
autologous, cell.
[0249] Regeneration can also relate to vascular, for example
coronary, parts employing such means with adapted stimulation for
coronary functioning.
[0250] In order to accelerate and prolong the multiplication
thereof in vitro or after transplantation, these cells or some of
them, for example myocardial or muscular precursor cells or others,
can be genetically modified so as to over-express telomerase or
Sir2 protein, in particular by transfection with a viral or
retroviral vector or other vector, of the gene of telomerase or
reverse transcriptase Sir2 protein (hTERT) by employing, for
example, the method described by Steven Goldman, Nature Biotech.,
Feb. 16, 2004.
[0251] The OIST according to the invention also applies to the at
least partial regeneration of the cardiac muscle, in particular in
patients suffering from chronic or acute heart failure, by
employing the OIST, even in the absence of cell contribution,
continuously or periodically for a long period of, for example,
from a plurality of weeks to a plurality of months or more.
[0252] The invention also relates to a process for preparing living
cells, in particular vegetable, animal and human cells, which can
be reimplanted prophylactically or therapeutically, wherein a
nucleus of a dedifferentiated cell is transported in an oocyte,
preferably an unfertilized or recently fertilized oocyte from a
homologous or heterologous mammal, previously preferably completely
or partially freed of its nucleus, so as to induce a stage of
mitosis of the transferred nucleus, in that this nucleus is removed
during the mitosis and before the end of it, then this nucleus
which is partially dedifferentiated in mitosis at this stage is
introduced into a cell, preferably after some part or the totality
of his nucleus or its nuclei have been removed from it, so as to
induce and terminate the differentiating nuclear division thereof
and to form a cell strain or a tissue at a less advanced stage of
differentiation than said differentiated cell.
[0253] The transferred nucleus can be extracted during the
metaphase, anaphase, prophase or telophase of the first
mitosis.
[0254] A nucleus of myocardial, muscle or cardiac auto-rhythmic
cell, in particular sinusal cells from the Tawara's node or fibers
from the His' bundle or Purkinje bundle can be transferred into the
oocyte.
[0255] The partially dedifferentiated cells obtained can be
subjected, preferably after or during the cell multiplication
culture thereof after the formation of a confluent assembly, to
periodic electrical stimulation of the cardiac stimulation type, in
particular by the stimulation process according to the
invention.
[0256] Preferably, said cells are subjected to coupled or paired
electrical stimulation in which that pulse without a contractile
effect is sent just after the end of the electrical refractory
period of the cells in culture.
[0257] For example, said cells are subjected to electrical
stimulation in cycles comprising a first stimulating pulse and,
toward the end of the refractory period, a pulse train, so that at
least one of the pulses of the burst falls just after the end of
the electrical refractory period of the cells and during their
mechanical refractory zone of maximum contraction.
[0258] The cells obtained by this process can be implanted in the
region of the auricular myocardium, in particular in the case of a
patient suffering from auricular fibrillation.
[0259] The invention also relates to an arterial segment or stent,
in particular with a coronary, aortic, carotid, renal or femoral
target, comprising a structure which is coated or colonized by
cells obtained by the process according to the invention,
preferably consisting of living, autocontractile and elastic, in
particular autologous cells, cultivated by the process.
[0260] This arterial segment or stent can be shaped in the manner
of an arterial stent arranged so as to be introduced into an
arterial lumen.
[0261] Preferably it comprises means for electrical stimulation of
the arterial type, coordinated with the ventricular diastole, of
said cells of the segment, for example at least one stimulating
and/or detecting electrode.
[0262] The stimulating and/or detecting electrode has preferably
been introduced into the cell culture so as to be surrounded by
said living cells.
[0263] The segment or stent can comprise a sensor, in particular
for measuring oxygen saturation and/or metabolic parameters and a
detecting or stimulating electrocardiographic sensor.
[0264] It can have a plurality of electrodes arranged for obtaining
variations in the local electrical impedance.
[0265] Preferably, it comprises a structure, in particular in
expansible meshes supporting different cell layers, such as
endoartery, myoartery and periartery structure, said structure
allowing a spontaneous increase with progressive widening of its
lumen and creation of vascularization which nourishes, in
particular, the myoarterial portion.
[0266] The structure is produced from at least one of the following
materials: PLGA, collagen, globin, for example by knitting.
[0267] It is also possible, for example, to provide an arterial
stent without living cells having a structure which is radially
expansible but sufficiently rigid to keep the arterial lumen open
at least in systole, which is optionally biodegradable or removable
by a catheter and capable of receiving a physiological stent as
described.
[0268] Finally, the invention relates to a biological cardiac
pacemaker comprising partially dedifferentiated auto-rhythmic
cardiac cells or tissues according to any one of examples 110 to
122 (which appear at the end of the written description hereof)
which is preferably autologous or homologous and originates from
the recipient's organism and is intended to be implanted in the
heart or in a defective region of the heart.
[0269] The invention will be described hereinafter with reference
to the accompanying drawings in which:
[0270] FIG. 1 shows schematically an electrocardiogram associated
with a mechanogram of the myocardium corresponding to the operation
of a device according to the invention;
[0271] FIG. 2 is a view of an actual example;
[0272] FIG. 3 shows the acquisition of various parameters during
operation of the device;
[0273] FIG. 4 is a schematic view of a cell implantation
device;
[0274] FIG. 5 is a block diagram of a device according to the
invention;
[0275] FIG. 6 is a schematic view of a device according to FIG. 5,
also having additional features.
[0276] FIG. 7 shows schematically the electrocardiogram and
mechanogram of an OIST according to the invention for a slow
spontaneous rhythm;
[0277] FIG. 8 shows schematically the electrocardiogram and
mechanogram of a bradycardizing OIST;
[0278] FIG. 9 shows schematically the various electrical and
mechanical zones distinguished in the invention;
[0279] FIG. 10 shows schematically the electrocardiograms and
mechanograms used in the stimulation according to the
invention;
[0280] FIG. 11 shows a control and display panel of a device
according to the invention.
[0281] FIG. 1 shows an example of the operating principle of a
device according to the invention. The upper line shows the ECG,
the median line shows the couplings Y of the orthorhythmic bursts
relative to the waves R of the basal rhythm, in other words as a
percentage of the duration of the earlier cycle Z and the lower
line shows the myocardial mechanical activity. The waves R in solid
lines show the spontaneous or stimulated depolarizations and the
waves RV in broken lines the basal waves R inhibited by the
artificial extension (ZR) of the refractory zones induced by the
bursts of electrical pulses. The stimulations in bursts of five
pulses of the stimulator according to the invention are shown
clearly on the ECG and the first pulse of each burst, which causes
depolarization, allows each functional refractory zone (ERZ of RZ)
in each cycle to be measured. It should be noted that the beginning
of the electrical non-refractory zone (ENRZ) precedes the beginning
of the mechanical non-refractory zone (MNRZ). On the mechanogram,
the interval MMRZ corresponds to the maximum contracted systolic
refractory zone which is still active and during which propagated
electrical stimulation causes in practice neither a myocardial
effect nor myocardial energy expenditure because this muscle, which
is in maximum contraction just before its active relaxation, is
incapable of any other expending biological action. The MMRZ is
followed by the mechanical non-refractory zone (MNRZ). It should be
borne in mind that any electrical stimulus occurring immediately
after the MMRZ, for example 20 ms later, falls in the MNRZ zone and
can already cause a premature biochemical energy recharging
reaction for this incipient diastole, leading to oxygen consumption
even in the absence of mechanical activity perceptible by current
instruments.
[0282] The MRZ or RZ interval corresponds to the mechanical
refractory zone preceding the narrow zone MMRZ. The zone MMRZ
corresponds only to a small portion of the peak of the ventricular
systolic pressure curve.
[0283] The reference character D designates the electrical
diastole.
[0284] The foregoing static description of the functional zones of
each cardiac cycle does not show the actual dynamic progress in the
region of a suffering myocardium. In reality, the various
functional zones and, in particular, the ERZ and MMRZ can vary from
one cycle to another, for example between 15 and 18 ms; this is
already partially promoted by cardioactive medicaments, the
vegetative dynamism and by the variations in the pre and post
charges, transmembrane fluxes and other intracellular metabolisms.
It will now be understood why the conventional paired stimulation
which uses only a single electrical pulse to prolong the ERZ, with
a constant coupling interval in ms, cannot produce an OIST of
clinical certainty because the only fixed coupling stimulus will
fall before, during or after the mobile critical interval, which
remains invisible on a normal ECG. This results in physiologically
inconstant cardiac stimulation, which is visible only on special
ECGs having a high speed of development and on very precise
intracardiac mechanograms (which are not found in conventional
coronary angiography), and specific metabolic requirements, leading
to an over-consumption of oxygen which is detrimental to the
myocardium, the hemodynamics and the eurhythmia and is wrongly
attributed to mere paired stimulation.
[0285] Not only the durations of the refractory zones but also the
excitability thresholds can vary during OIST cycles treated by the
invention with paired or coupled stimulation. To instantaneously
and continually compensate for these irregularities, an automatic
device for instantaneous readjustment of these thresholds which are
well-known in the field of implanted cardiac stimulators first
described by the inventor in his French patent No. 1,237,702, P.V.
No. 651 632 of Jul. 11, 1953, should be provided. It may be
beneficial to launch periodically and automatically on demand,
depending on the frequency of the critical variations of the
observed thresholds, orthorhythmic bursts of which the voltage
varies progressively or otherwise and of which the effects on the
electrical depolarization caused will automatically be taken into
consideration for readjusting, for example, the intensity of the
pulses making up each burst in the next cycle concerned. In
addition, this intensity of the pulses can vary regularly or
otherwise from one pulse to the next or periodically within each
burst of the OIST. In the case of specific significant variations
in these excitability thresholds or refractory zones, it is
desirable to automatically check whether the variations merely
relate to one of the parameters and which, or whether both
parameters vary together and how. These checks also allow an
instantaneous preventive reaction if it is impossible to continue
stimulation (OIST) according to the invention as programmed, for
example in the case of metabolic disorders (incipient local lack of
oxygen, tendency to arrhythmia, lowering of hemodynamics, etc.). In
the more frequent cases of OIST, which remains sufficiently stable,
the number, the density (a plurality of electrodes or a large-area
electrode emitting by focusing on a receiving electrode), the width
or the intensity of the pulses of each burst of the new
orthorhythmic pacemaker can, for example, automatically be reduced
or, conversely, be increased in the case of increasing instability.
It is thus possible to obtain automatic exploration of each cardiac
cycle which is continuously adapted to its own pathophysiological
development and allows numerous cardiac failures to be
instantaneously prevented, treated and notified, these cardiac
failures otherwise being revealed later or too late. In addition,
this process can allow the instantaneous control of specific
implanted medical pumps (Zacouto, U.S. Pat. No. 5,305,745) and, if
there are a plurality of electrodes, which are preferably quite
spaced, for stimulation in the heart (for example, ventricular
resynchronization stimulation), a sudden adequate difference
between these refractory zones and the excitability thresholds can
indicate a coronary thrombosis or local myocardial lesion. The
diagnostic functions of the OIST according to the invention can
themselves justify the application thereof, for example when using
drugs which influence cardiac function, as required by cutting off
the stimulation functions.
[0286] A distinction should be made in clinical use of OIST
depending on whether it is applied to tachycardia or myocardial
failure. In the case of poorly tolerated, refractory or recurrent
tachycardia, OIST allows, after installation of the cardiac
stimulation electrodes, the rhythm thereof to firstly be reduced
rapidly by approximately two-fold with a considerable immediate
increase in the heart output, which is due on the one hand to the
great prolongation of the diastole and, on the other hand, to the
PESP which is added thereto. In certain clinical cases, in
particular ventricular tachycardia (VT), it is possible to
eliminate this tachycardia by cutting off their reentrant circuits
by the adjustable orthorhythmic bursts of the OIST which can
automatically target the smallest myocardial spaces not yet in the
refractory phase during ectopic depolarization. It is not always
enough to subject a VT to OIST in order to reduce it, but once
installed, its orthorhythmic parameters must be varied, for example
the pulse intervals, the numbers, intensities and widths thereof,
the coupling percentage relative to the duration of the earlier
cycle, etc. of the bursts must be brought closer together and, if
necessary, the stimulating electrode must be brought closer from
the starting point of the ectopic activations; all this can be
achieved and stored automatically, for example relative to the
marking spikes of the detections and stimulations of the
orthorhythmic pacemaker (ORP), if there are a plurality of
electrodes which thus allow an electrical shock to be avoided. In
the case of acute or chronic cardiac insufficiencies not caused by
rapid ectopic tachycardia, which are frequent in moderate
sinusoidal tachycardia, the OIST immediately causes a reduction in
the rhythm (for example 100 per min to 60 per min) and a
significant lasting increase in the cardiac and coronary output as
well as an immediate lasting reduction in the pulmonary arterial
pressures. it can preferably
[0287] In the event of irreducible or recurrent tachycardia, in
particular VT, the rhythm thereof can be reduced by half by using a
continuous OIST, and this can be an alternative to an ablation or
can allow one to expect an ablation under excellent hemodynamic
conditions, without danger to the patient, and this cannot be
achieved even by a return to the sinusal rhythm. In wearers of an
implanted automatic defibrillator (IAD) it is possible on the
occurrence of a dangerous, resistant or excessively recurrent
tachycardia during conventional orthorhythmic anti-tachycardic
stimulation, to switch firstly to an OIST and, only if good
hemodynamics are not re-established after about 10 seconds, to
trigger the defibrillation shock; this procedure will allow painful
shocks to be eliminated. In the case of acute or chronic cardiac
failure, not caused by rapid ectopic tachycardia, which are
frequent in moderate sinusal tachycardia, the OIST immediately
causes a significant lasting increase in the cardiac and coronary
rate as well as a lasting reduction in the pulmonary arterial
pressures. A further advantage of the implanted OIST is that it
generally allows the patient to resume much greater physical
activity. The abrupt significant increase in hemodynamics caused by
an OIST can be a drawback for some patients; in these cases the
OIST can be programmed not to launch its bursts or pulses
prolonging the zones ERZ for example only at a spontaneous or
stimulated wave R at three or four instead of one in two or again
to reduce the duration of the diastoles by accelerating the basic
rhythm. For example, the mode of paired stimulation of the OIST can
be switched automatically to coupled stimulation by the
intervention of a program entailing an increase which is strictly
limited by a selected threshold. A coupled stimulation is a
stimulation without any spontaneous wave R at a rhythm which is
totally imposed by the OIST. These two modes can occur
automatically if they are controlled relative to the parameters of
the desired hemodynamics and preferably by controlling the
concomitant metabolic changes such as the oxygen consumption.
[0288] A further known advantage of the orthorhythmic pulse bursts
used by the OIST is that, with a burst, for example, of four
successive square pulses having a duration of 0.5 ms each at 1.4
volts with a pulse interval of 15 ms, if the second pulse causes
depolarization, the following pulses will rapidly exceed
(propagation rate exceeding several Km/sec) possible fibrillation
which has been beginning locally for less than 15 ms (propagation
rate of approximately 70 cm/sec) and will surround it with a
refractory zone; in addition, the first pulse of the burst which
falls in ERZ eliminates the propagation of possible depolarizations
of a few earlier cells which are invisible on the ECG but can
sometimes trigger an arrhythmia.
[0289] In addition, the OIST immediately improves the coronary
flow, particular by intervention of the EPR and by the highly
elongated diastole, as known in coronary angiography and by the
motor beginning of the diastole which is increased proportionally
to the potentiated shrinkage of the myocardium caused by the
intensified contractility which corresponds to a marked increase in
the viscoelasticity of the myocardium during the motor phases; this
viscoelasticity is measurable, for example, by a multiaxial
pressure detector implanted in the myocardium, such detectors being
known. The concomitant drop in the pulmonary arterial pressures is
probably due, in particular, to the rise in heart rhythm. In
theory, the OIST should not lead to a significant additional
expenditure of oxygen. The significant deceleration of the
ventricular rhythm reduces this oxygen consumption whereas the
increase in contractility demands an oxygen supplement, despite an
improved energy output. A specific increase in oxygen consumption
during the OIST also corresponds to an increase in the ratio of
heart output to consumed oxygen output; the sudden increase in the
coronary flow will usually allow this supplementary oxygen
expenditure to be tolerated well. With equal increase hemodynamics,
the OIST consumes less oxygen than the other heart rhythms. There
are extrasystolic spontaneous ventricular rhythms with optimum
hemodynamics which function as a paired artificial stimulation as
if the maximum contraction causes a targeted electrical
extrasystole for protecting the myocardium from a next contraction
which is too close (FIG. 2) recorded by the inventor and published
(Dtsch. Gesellsch. Kreislauff. 29 Congress, pp 255-261, 1963
Steinkopff Verlag Darmstadt). A further example of spontaneous
rhythm resembling a paired stimulation is the electromechanical
decoupling, one QRS in two, in the event of rapid tachycardia; this
phenomenon can last for years, and patients are often well and are
surprised when their tachycardia is revealed to them.
[0290] The OIST according to the invention aims to take optimum
control of the rhythm and contractility of the heart, on the one
hand, by occupying the very first beginning electrical
non-refractory zone of a cardiac cycle and, on the other hand, by
attempting to assure optimum contractility and a desired blood flow
per minute; this last contention necessitates geometric and/or
volumetric and energy control in real time of at least one cardiac
ventricular cavity. For this purpose and for ORP with OIST, whether
or not implantable, it is preferable to provide a device demanding
little energy, for example of the intracardiac electrical impedance
measuring type. The parameter of development of the volumetric
variations is preferably completed by that of the intracavitary
blood pressures and/or concomitant intramyocardial pressures, in
order to reproduce a correct pressure/volume curve which can
preferably be displayed at the exterior of the body by conventional
telemetry. For an automatically programmable stimulator of this
type, it is possible to produce an electronic device which
incorporates, for example, the areas of the pressure curves and, if
possible, corresponding volumes and rates and blood flows (for
example by intracardiac electrical impedance measurement type),
relative to the programmed ventricular rhythm, and which then
entails a rhythm close to the value which detected the most
favorable hemodynamics for a given patient at a given moment, after
having performed, stored and compared these values obtained after a
specific frequency scanning (Zacouto, U.S. Pat. No. 5,306,293). In
addition, automatic adjustment of the pulses constituting the
orthorhythmic stimulating burst relative to the hemodynamics and/or
to the oxygen consumption can vary the number of pulses, throughout
their interval, which may be non-equidistant, their width, their
shape, their polarity, their intensity and their voltage which may
also be unequal as well as the location of the application thereof
in the heart region. This location of their application can
comprise fixed or variable monopolar, bipolar or multipolar
stimulations with endocavitary, intramyocardial, epicardial,
auricular or ventricular electrodes or coronary intravenous,
coronary intra-arterial or intra-stent electrodes such as special
stents with ECG and/or stimulating electrodes with or without
hemodynamic sensors or sensors of oxygen and/or CO.sub.2
saturation, pH, glycemia or other metabolic indicators. To avoid a
high expenditure of energy by the electronics of these implanted
apparatus, a small HF aerial can be installed on either side of the
skin to transmit additional energy when the apparatus uses special
therapeutic sensors and effectors.
[0291] The control of the heart rate by the OIST according to the
invention allows an accelerated heart to be accelerated and also
decelerated, and this also distinguishes it from conventional
cardiac pacemakers. In the event of OIST-induced relative
bradycardia, the electrical non-refractory phases are less
prolonged than with spontaneous bradycardia. If it is not possible
to obtain the desired adjustment of the accelerated ventricular
rhythm with the paired stimulation, the OIST can automatically pass
to ventricular coupled stimulation and this eliminates any
spontaneous QRS complex and allows an effective ventricular rhythm
which is half of the stimulated rapid ventricular rhythm to be
obtained. If the atria and Hisian conduction are normal, the atria
can be brought to a rapid rhythm of approximately 160 per min and
ventricular OIST can be obtained at about 80 per min, as
successfully achieved on two patients suffering from cardiac
failure, and this enables a driven but quasi-normotropic to
continue in its activation, as viewed from the ventricle.
[0292] Outside regular tachycardia, the reduction of the
non-refractory phases in the myocardial space produced by the OIST
and its adjustments give this cardiac stimulation an
anti-arrhythmic effect, in particular for eliminating early
ventricular extrasystoles. In the event of auricular fibrillation
(AF), the ventricular OIST could allow the ventricles to be
protected from the influxes of the AF completely in the case of
influxes of the AF which fall early in the ventricular cycle (VC)
and partially in the case of the influxes occurring later in the
VC, if necessary by potentiating with specific drugs which
decelerate His' conduction, and this gives back to the ventricles a
sufficiently regular rhythm, for example eliminates all VC of less
than 600 ms, which is partially adjustable and accompanied by
optimum contractility; this can compensate and over-compensate the
unfavorable effect of the AF on myocardia which are fatigued by
tachyarrhythmia and low coronary flows and can optionally
potentiate the effect of digoxin and other cardioactive
medicaments.
[0293] A ventricle can also be stimulated toward 150 pulses per min
and obtain, by OIST according to the invention, an effective
regular rhythm of about 75 pulses per min which is well tolerated
and sheltered from the influxes of the AF. An auricular OIST
increases the auricular contraction to a maximum and potentiates
its muscular power, opposes the dilatation thereof, thromboses, the
reinstallation of specific AF (auricular fibrillations) and
improves the ventricular and coronary flows if the parameters of
the OIST are well adjusted relative to the natural or artificial
auricular and ventricular activations. An auricular stimulation
can, for example, be achieved in bipolar mode using electrodes
placed on the upper half of the auricular septum and capable of
helping to synchronize the atria without affecting the ventricles.
A double coordinated auricular and ventricular OIST which increase
the coordinated auricular and ventricular contraction to a maximum,
may be very beneficial, with or without His' partial blockage, for
considerably increasing cardiac hemodynamics without delay and for
a long time.
[0294] Any OIST adapted according to the invention regenerates
genetic functioning with inotropic effect of the myocardium with
changes of developmental gene expression, ion channels and
contractile functions induced by the increased mechanical and
metabolic stresses imposed; they will lead to its intracellular
remodeling of functional recovery, for example in the event of
cardiac failure (dilatations) or necroses (shrinkages). This
etiological therapy of each cardiac failure can give a rapid
genetic involution of its pathological process and genetic change
of physiological and anatomical regeneration caused by the effect
of the highly increased contractility to the specific evolutive
possibilities of each patient, automatically adapting to each
particular case unless specific illnesses, such as metabolic,
tumoral, viral, toxic, etc. illnesses prevent myocardial function
from re-establishing. The maintenance of cardiac function
re-establishment demands adequate peripheral muscular activity
which should be coordinated with the central myocardial action of
the OIST.
[0295] For specific expansive necroses or fibroses of the
myocardium, the local autologous grafting of stem cells which are
multiplied and differentiated in vitro or of cells which are
genetically modified or reprogrammed by mechanical, electrical and
biochemical driving capable of recolonizing the destroyed sites and
metabolizing specific scar tissues can be envisaged.
[0296] It is possible to proceed with the mere local recolonization
of partially dedifferentiated isolated cells of myocardium, which
is a syncytium, cells which are genetically oriented toward
rhythmic and contractile functions with refractory zones which can
easily organize themselves, owing to the effect of the environment,
into mechanically powerful networks which are well coordinated with
the heart.
[0297] Preferably, prior programming of the OIST will be added. The
in vitro multiplication of the cells to be grafted need not always
take place in the immobile state, but preferably also under a
controlled alternating mechanical stress which is adapted to the
future functions of the cells and capable of inducing an
electrophysiological membrane state which is compatible with the
function of the heart to be served and is preferably controlled by
an OIST adapted to the functional capacity of the cells so as to
orient them genetically toward their future contractile function,
if possible with autologous serum.
[0298] In addition, these cells should be incited not all to
multiply separately but, for example, to form small functional
structures in three dimensions by cultivating them, for example, on
a pre-formed, porous, elastic and biodegradable matrix such as PLGA
and PLA (polylactic acid derivatives) so as to avoid the
dissemination thereof after the injection thereof and to promote
the contractile function thereof in a syncytium coordinated with
the stimulation of the heart. The small preformed matrices may have
3D shapes which promote their assembly with one another and with
the recipient's myocardium, for example in the form of strips,
discs, squares, crosses, serpentines, etc. Electrophysiological
analysis of these cells should also be carried out prior to
implantation, for example by means of intracellular
microelectrodes, to verify the refractory zones and the action and
membrane potentials and to check their motor capacity, for example
by measuring the deformations of their elastic matrix. These cells,
which are prepared for their contractile function, can also serve
in the case of AF to form a myocardial tissue which can be
implanted in the atria and can be produced, for example, through a
catheterized venous channel under at least echocardiographic
control, the probe or probes also being able to pierce through the
auricular septum and also seed the left atrium; this
sub-endocardial seeding of groups of implanted myocardial cells
either one by one or as a bridge between a plurality of roots with
care to avoid perforating the wall and detachable protrusion in the
auricular cavity, can be carried out using an orientable catheter
equipped at its end with a cylinder containing a narrow flexible
pointed retractable tip of the catheter sliding on the endocardium
and raising the endocardium by aspiration and pricking it very
slightly at this point by pushing a cylinder of cells to be
implanted (CLI) into the small fissure obtained by means of a
piston which is fully pushed and is retracted against the catheter
walls, for example in the form of a valve with resilient lips moved
by the pressures or by means of an inflatable and deflatable
balloon capable of disconnecting the CLI, the retraction or
deflation revealing a new "cylinder" of cells of which the length
can be adjusted from the exterior in front of the piston or balloon
in the catheter by pressure of a fluid (FIG. 4). The groups and
bridges of implanted cells (CLI) will expand and form a network of
contractile meshes controlled by a mere OIST or stimulation, for
example situated in the right atrium and the CLI, owing to their
proximity, should fuse in the original syncytium where they induce
certain parts of their genetic equipment. A cell implantation
catheter of this type can be applied to any region of the heart and
other organs such as kidneys, pancreas, liver, etc. This principle
of implantation of multiplied autologous cells capable of
multiplying easily and prepared for a contractile function can also
be applied to the construction of a complete or partial artificial
heart formed at least in part by autologous cells cultivated,
preferably, from partially dedifferentiated myocardial cells.
[0299] In a preferred embodiment of the invention there is carried
out partial cellular therapeutic cloning which consists in
introducing into a denucleated oocyte, a total or partial foreign
nucleus and removing this nuclear material at a desired incomplete
stage of its mitosis and then implanting it in a preferably
autologous, differentiated cell which is denucleated or otherwise
and in which the initial mitosis will end, leading to partial
dedifferentiation.
[0300] Purely nuclear partial cloning involving removing the cell
nucleus during selected incomplete mitosis of the oocyte before the
initial complete cell division at a given instant by analysis, for
example optical analysis, of the development of the nucleus can be
considered. Thus, for example, during the prometaphase, if light
dedifferentiation is desired or, during the anaphase or the
telophase, if more pronounced differentiation is desired. Next, it
will be introduced into a living cell membrane which is preferably
emptied of its nucleus and is preferably autologous, embryonic or
from stem cells, for example dermal, epithelial, lymphatic,
conjunctive, osseous, cartilaginous, blood or muscular cells. These
cells, resulting from incomplete cloning, could then be introduced
into a myocardial cell where it can perform regenerating genetic
transcription and expression capable of inducing, at least locally
and temporarily, in its environment, partial genetic action and
contamination to the desired extent.
[0301] In a variation of the invention, a nucleus which is already
undergoing incomplete mitosis or even complete mitosis,
spontaneously or by known artificial provocation, can also be
introduced in the form of two initial cells in order to obtain
partial dedifferentiation more easily.
[0302] In view of the rarity of human or mammalian oocytes, it is
considered to render an oocyte multiparous by introducing into it a
new nucleus after having delicately removed the first nucleus which
is undergoing partial mitosis. This multiparity by successive
intraoocyte inoculation may have a dedifferentiation effect on the
nuclear material which is different from that obtained during the
initial introduction of the nucleus or chromosomes or genes of this
same oocyte.
[0303] A nucleus which is, for example, already undergoing partial
spontaneous or induced mitosis, or otherwise chromosomes or genes
or a part of nuclei to be treated in an embryonic cell can also be
introduced into the oocyte. This will preferably be of the same
tissue, for example myocardial tissue, preferably partially
denucleated and cultivatable in vitro, in vivo or in situ. The cell
or cells will be cultivated for multiplication, preferably for
sufficiently long in vivo in embryonic tissues to obtain partial
dedifferentiation. The nuclei thus treated may be left, either in
the embryonic cells to constitute a tissue which can be grafted
into the organism originating from the nucleus or extracted from
their accommodating cells so as to induce local cell regeneration
in the region of a differentiated, preferably autologous and
identical tissue. Implantation of the nucleus or nuclear portions
can also take place within a stem cell, preferably of the embryonic
or fetal type.
[0304] Partially and selectively dedifferentiated cells of this
type may then be introduced into surviving myocardial cells which
are preferably original and have preferably been more or less
denucleated and can act as regenerating myocardial tissue to be
implanted, for example, in regions which have been subjected to
sclerosis by fibrosis and are poorly vascularized or regions of the
heart having inadequate contractility.
[0305] From a certain degree of dedifferentiation, these cells lose
their immunogenic power and can be used to regenerate
non-autologous myocardial tissues.
[0306] This function also comprises the capacity of these
genetically activated cells to act remotely by secretion,
liberation or induction, in particular through specific biochemical
molecules. This transhumoral genetic activation shows, among other
things, the capacity to mobilize locally appearing pro-generating
cells as observed in extensive myocardial infarction.
[0307] This cell preparation, which also applies to other cell
types, can create controlled regeneration tissues for treating
numerous organic and tissue lesions. Thus, for example, by
removing, under echographic control using a transrectal needle,
prostate cells which will be totally or partially cloned and by
reinjecting them by the same method into the prostate, this
inducing cell rejuvenation could, in certain cases, impede the
development of local cancer or decelerate the spreading thereof.
Also, a regenerated autologous, or even homologous, ophthalmic
retina could be of great benefit in the event of DMLA, and serious
renal failure could be combated by implantation of partially
dedifferentiated cells obtained, after transfer into and then from
oocytes, from nuclei of various nephron cells, and arthrosis could
be relieved by the implantation of chondrocytes originating from
partial cloning; the same applies to cutaneous surfaces and, in
particular, to the regeneration of normal hair, for example by
transferring one or more nuclei or parts of nuclei of hair follicle
and/or melanocyte cell nuclei into the oocyte, for regenerating
hair and/or its colour.
[0308] A significant application of the invention is in
potentiating or recreating thymus functions by genetic rejuvenation
of homologous or, if possible, autologous, partially
dedifferentiated thymus cells in order to actively reanimate the
immuno-protective functions of the body.
[0309] In the event of auricular fibrillation, a main application
of the invention involves transplanting these partially
dedifferentiated cells which are functionally driven to
synchronized contraction in a laboratory by implanting them, for
example, in sheets or in grids in contact with the auricular
myocardium where they are able to progressively multiply and/or
grow and/or genetically modify the diseased cells of the auricular
myocardium and/or else also act by secretion and humoral
biochemical, mechanical or physical induction activity, perhaps by
intervening in a morphogenetic field.
[0310] In an advantageous embodiment, a myocardial cell is excised
under a microscope, and the membrane and the cytoplasm living in
culture after one, more or all of the nuclei have been extracted,
are kept. This or these extracted nucleus or nuclei will be
introduced individually or in a group into one or more preferably
previously enucleated oocytes, and only the pro, meta, ana or
telophase will be awaited, preferably by observation under a
microscope, before removing them and reintroducing them into the
membrane, and the conserved cytoplasm which is living or capable of
living in culture or in another myocardial syncytial cell,
preferably emptied of some or all of its nuclei.
[0311] These cells with more or less dedifferentiated nuclei will
be placed in appropriate culture and multiplied, preferably on
biodegradable resilient stents, for example a collagen matrix or a
resilient fabric which is biodegradable in vivo, and will be
stimulated, preferably progressively, by a simple or inotropic
orthorhythmic pacemaker in order to adapt physiologically to their
future insertion, either in the patient's diseased or senile
myocardium, or to constitute the self-contracting walls of a
partial or total artificial heart, and will subsequently be
implanted in the patient, in particular also in the auricular
region so as to suppress auricular fibrillation, in particular also
to form segments of active contractile coronary arteries that can
be used as physiological conducting and propelling coronary stents,
this complementary coronary contractility and active and passive
distensibility being able to be induced as required by electrical
arterial stimulation of the arterial smooth muscle offset in a
diastole relative to the ventricular contraction or to form an
almost complete or supplementary coronary artery, for example being
able to originate from partial differentiation or cloning of
autologous muscle arterial cells and also coronary endothelial
cells reconstituting a functional rejuvenated autologous coronary
artery optionally on resorbable or other resilient or extensible
stents.
[0312] In a variation of the invention, a selected portion of a
chromosome or a complete chromosome or gene is introduced into a
suitable functional oocyte, either individually or accompanied by a
portion of the nucleus or of the differentiated cell nucleus, which
are preferably original or non-original autologous, partial or
complete, to be treated. These nuclei to be treated can be
selectively depleted in the disease chromosome or chromosomes which
are to be replaced so that the nucleus will tolerate its selective
and/or partial dedifferentiation genetic chromosome
reconstitution.
[0313] A gene or a group of genes may obviously be substituted for
the portion of chromosomes or for all the chromosomes to be
dedifferentiated without departing from the scope of the
invention.
[0314] One or more groups of genes can thus be transplanted into a
suitable oocyte in the presence or absence of a selected assembly
of chromosomes or of at least one cell nucleus of which the
selective and partial dedifferentiation, for example during the
metaphase or anaphase, will allow precise monitoring by remote
optical microscope observation, the chromosomal reorganization for
the preparation of the cell division allowing the isolation of the
chromosomes and the selective destruction of one or more
chromosomes or chromosomal regions, for example by laser radiation
in a manner known per se and their replacement by one or more
healthy chromosomes or corresponding regions and will then allow
the thus modified nucleus to be subjected to partial
dedifferentiation in an oocyte.
[0315] The partially dedifferentiated nuclei or chromosomes could
be extracted, for example, by intra-oocyte injection of a suitable
serum under slight pressure after having sufficiently mobilized the
nuclear material with a micro-rod or paddle or by vibratory
ultrasound or laser action.
[0316] A check can easily be carried out by the degree of nuclear
or perinuclear integration, this integration being optically
visible.
[0317] In the case of the creation of complete or partial
artificial or artificially induced chromosomes or genes, these
elements should often be subjected to partial dedifferentiation of
this type in order to create for them a history of genetic
development without which their future could be compromised. If
these artificial elements with genetic function do not tolerate
genetic dedifferentiation involution, their future functionality is
uncertain.
[0318] Tissue grafts require, for their success, the adequate
elimination of serious rejection lymphocyte reactions which are
generally of the antigenic, antibody and humoral type in the
recipient organism, as observed in pregnant women who biologically
tolerate their fetus through their placenta. For example, these
characteristics of tolerance, in particular lymphocyte tolerance
and the functions of the thymus are to be genetically and/or
plasmatically imitated, for example. In adult and, in particular,
aged humans, the presence of the thymus cells and functions is
often too weak or event absent. It may be beneficial, for example,
to transplant a homologous thymus tissue which is partially and
selectively dedifferentiated and genetically adapted, for example,
by selective chromosomal integration of chromosomes of the graft in
cell nuclei of the receiving organism, either by genetic
preparation of blood stem cells of the receiving organism or by
preparation in in vitro or in vivo cell culture (such as sub- or
intradermal) with or without hyperexpression of their telomerase or
protein Sir2 in order to prolong their life and bring about their
induced habituation to the critical antigen and antibody of the
cells to be grafted by the known means of the influence which is
induced remotely by biochemical and hormonal substances on the
expressions of specific genes.
[0319] Cells of this type which are genetically adapted to various
receiving tissues can be used, in particular, for the radical cure
of auricular fibrillation and for retinal regeneration,
implantation of pancreatic tissue without protective membrane, of
regeneration nephrons, of intercerebral dopaminergic cells against
Parkinson's disease, of dermal and epidermal regeneration tissues,
including hair, of prostate or mammary gland tissues for curing the
corresponding cancers and, in particular, regenerating thymus cells
and any other cells which function in a beneficial or indispensable
manner, in particular the digestive, nervous, dermal, respiratory,
skeletal and cardiovascular ducts and systems.
[0320] Coronary, carotid, renal, etc. arterial lesions may be fatal
and ideally necessitate radical tissue and function regeneration
treatment. For this purpose, the invention comprises a variation
which is capable of removing autologous or homologous arterial
muscle cells and subjecting them to controlled partial
dedifferentiation by the above-mentioned methods. These arterial
cells can then be cultivated either in vitro around a preferably
resilient, dissolvable or non-dissolvable stent in the form of a
tube and in a serum circulating within a tube under pulsatile
pressure which progressively increases so as to recreate the
contractile and elastic relaxation function of the cells in order
to reconstitute an arterial tube of the desired diameter. Partially
dedifferentiated arterial endothelial cells will similarly be
cultivated in the form of a smaller diameter tube which will
finally be introduced into the largest tube cultivated in this way.
Partially dedifferentiated arterial segments of this type which are
tolerated by the organism could then either replace diseased
arterial segments or be implanted alongside or instead of a
defective network.
[0321] On the scale of coronary arteries, living auto-contractile
"stents" for example which can be implanted, for example by
endoarterial catheterization, can thus be created. Current stents
are made of an inert immobile plastic or metal material and replace
a more or less auto-contractile but thrombosed arterial segment,
contributing to the depopulation of downstream small arteries and
coronary capillaries. These artificial stents not only lack active
action such as coordinated blood propulsion with the local motor
arterial wave, but also disturb the dynamics of the normal blood
flow of all of the artery concerned, often leading to depopulation
of the small vessels downstream of the stents.
[0322] On the other hand, as a living autologous reconstituted
physiological coronary artery segment which is actively pulsating
while potentiating the arterial shower and is if necessary
genetically "rejuvenated" by partial dedifferentiation does not
cause rejection reactions by the organism receiving the graft, it
can reconstitute a very active physiological arterial segment which
may additionally be capable of improving blood circulation of the
entire artery, for example owing to its mechanical capacity
(calling upon the mechanical sensitivity of specific genetic
expressions) and owing to genetic secretions and induction of
factors capable of remotely inducing a specific cell
rejuvenation.
[0323] Normally, this "pulsatile physiological stent" will be
activated spontaneously, in particular by the variations in
parietal and blood pressures. If necessary, the coordinated
rhythmic activity of this segment of "physiological stent" can be
assured by an arterial electronic pacemaker adapted to the rhythm
of the arterial beat, for example by a detector of ventricular or
intramyocardial intracavitary pressures and/or the ECG and
stimulating during the diastole, for example also relative to the
rhythm of the cardiac pacemaker.
[0324] A sensor of pressures, of the oxygen saturation and of the
ECG can also be placed on such an arterial stent, preferably toward
its distal end, during in vitro tissue reconstruction, these
sensors thus being totally surrounded by living tissue, and can
connect the output wires, preferably to the cardiac pacemaker or
implanted defibrillator so that the effective local blood
circulation will be known continuously, without carrying out
instantaneous radioscopy with injection of contrast substance.
[0325] In order to maintain the requirements of an emergency
operation for positioning a conventional stent, an immobile stent
which is progressively dissolvable or removable or infiltrable by
the "physiological coronary reactivation stent" should be implanted
urgently by catheterization.
[0326] In a preferred variation of the invention, this
reconstituted coronary arterial segment is provided, in living
continuity, with arteries, arterioles, capillary and venous
networks with their irrigated myocardial tissues; this functional
tissue block being previously cultivated and multiplied in vitro or
in vivo, preferably from autologous, partially dedifferentiated
cells, an adequate venous join of this tissue being provided toward
the ventricular cavity or the coronary venous sinus. This highly
functional renovated myocardial unit can progressively induce
recolonization of the capillaries and small coronary arteries of
the original myocardium.
[0327] The implantation of a physiological stent by conventional
arterial catheterization will initially operate by imbibition of
arterial blood supply, as performed during the culturing thereof,
from the endoartery.
[0328] The high vitality of the renewed physiological stent will
progressively create new vaso-vasorum. The dominant vitality of
this arterial segment will subsequently produce a degree of
widening of the caliber of this stent as a function of its
metabolic requirements.
[0329] An additional application of the invention involves
progressively reconstituting in vitro preferably after partial
dedifferentiation of the initial cells of various cardiac tissues
and the incipient multiplication thereof, a portion of ventricle,
for example in the case of ventricular aneurysm or necrosis or all
of two ventricles, using extensible or fairly flexible or
biodegradable carriers and suitable growth factors and while
respecting the ventricular geometry in three dimensions so as to
produce vascular connections of the type which can be obtained from
echocardiography in three dimensions (N. Mirochnik, A. Hagege, F.
Zacouto and C. Guerot: Arch. Mal. Coeur, Paris, 93, Oct. 10,
2000).
[0330] In other variations, the invention can be applied to cell
and tissue grafts without serious rejection reactions by the use of
partial and/or selective cloning.
[0331] In a variation of the invention, a selected portion of a
chromosome or a complete chromosome is introduced into a suitable
functional oocyte either individually or accompanied by one or two
preferably autologous partial or complete cell nuclei from the
recipient or non-original to be treated. These nuclei to be treated
can be selectively depleted of one or more diseased chromosomes, in
particular which can be isolated during a phase of their mitosis,
which are to be replaced by equivalent chromosomes preferably of
the embryonic or genetically partially dedifferentiated type so
that the nucleus will tolerate its selective and/or partial
dedifferentiation genetic chromosome reconstitution.
[0332] One or a group of genes can obviously be substituted for the
portion of chromosomes or complete chromosomes to be
dedifferentiated without departing from the scope of the
invention.
[0333] One or a group of genes can thus be transplanted into a
suitable oocyte in the presence or absence of a selected assembly
of chromosomes or of at least one cell nucleus of which the
selective and partial dedifferentiation, for example during the
metaphase or the anaphase, will allow, by remote optical microscope
observation, precise monitoring of the chromosomal reorganizations
in preparation for cell division by means of movements and
appearances of the intracell elements or centriolar nuclear
elements, the beginning of formation of a nuclear membrane,
movements and densification of chromosomes, etc. In other words,
groups of genes or selected chromosomes should be sufficiently
dedifferentiated beforehand and then transplanted into a
nucleus-carrying oocyte which should be genetically modified and
previously deprived of the diseased chromosome or chromosomes
concerned.
[0334] A variation of the invention consists in partially
co-dedifferentiating in a same or autologous denucleated oocyte to
induce reciprocal immune tolerance between, on the one hand, a cell
nucleus of which one or more diseased or senile chromosomes or
parts of chromosomes have been destroyed during the mitosis thereof
and, on the other hand, one or more healthy portions of chromosomes
or complete chromosomes, preferably homologous, healthy younger
chromosomes. Cells of this type which have been genetically
repaired and dedifferentiated can also receive an over-expression
of their telomerase or Sir2 protein.
[0335] The partially dedifferentiated nuclei or chromosomes could
be extracted, for example, by intra-oocyte injection of a suitable
serum under slight pressure, after having sufficiently mobilized
the nuclear material with a micro-rod or paddle and/or the
application of local vibratory ultrasound or laser action.
[0336] The degree of nuclear or perinuclear integration could
easily be checked, this integration being optically visible.
[0337] In the case of the creation of complete or partial
artificial or artificially induced or disposed chromosomes or
genes, these elements should often be subjected to partial
dedifferentiation of this type in order to create for them a
history of genetic development without which their future could be
compromised. If these artificial or artificially combined elements
with genetic function do not tolerate a history with targeted
genetic dedifferentiation, their future functionality is
uncertain.
[0338] A practical example of the process can be to acquire the
hemodynamics and optionally the corresponding oxygen consumption
and then to determine the intervals of couplings of the paired
stimulation relative to the R wave of the ECG in ms or relative to
the R--R interval as a percentage of the duration of the earlier
cycle, or by an algorithmic combination of the two. A pulse train
is transmitted for at least one cycle. The hemodynamics for one
cycle are acquired and are compared with the spontaneous
hemodynamics while checking that the increase obtained exceeds a
programmed percentage, for example 20%. If the desired values of
hemodynamics and optionally of oxygen consumption are attained,
this OIST is continued and the acquisition of the hemodynamics and
preferably of the myocardial oxygen consumption is continued. If
the programmed values are not attained, at least a parameter of the
pulse trains is modified and the checks are repeated. If the
desired values are not obtained after the successive programmed
changes of the parameters of the pulse trains, the OIST is
stopped.
[0339] FIG. 5 shows, by way of example, a block diagram of an
implanted device according to the invention.
[0340] The technical embodiment of the various hardware or software
components will not be described in greater detail, whether they be
the detection or stimulation means, the energy sources and the auto
processing and memory means, as they are all quite conventional and
well known in implanted stimulators nowadays.
[0341] The device comprises electrical detection and stimulation
means 1. For example, detection electrodes which can also be used
for stimulation, as is often the case. Detection means supply the
acquisition means of the electrocardiogram 2 with signals. These
acquisition means allow, in particular, the heart rhythm, namely
the RR intervals of the muscle contraction generating waves and
R--R', in other words the interval between the wave R and a coupled
wave R' induced in accordance with the invention at the end of the
refractory period to be obtained and stored in the logic means 3
(K. Theisen, F. Zacouto, M Grohmann, H. Jahrmarker:
Refraktarzeitmessung bei absoluter Arrythmie mit orthorythmischer
Serienstimulation, Klin. Wochenschr., 52, 1082-1084 (1974)
Springer-Verlag). These means also allow determination of the
pulses of the pulse burst which caused the wave R'.
[0342] It is thus possible to obtain the determination of the
refractory period at 4.
[0343] The device also comprises hemodynamics detection means 5
such as an intracardiac or intramyocardiac pressure sensor and
impedance measuring volume sensors, and means measuring the kinetic
energy of each expelled volume (for example by measuring the
gradient .DELTA.p/.DELTA.t of the pressure and/or volume
variations, or again by Doppler effect implanted sensors or
accelerometers, these means allowing, in the means 6, the
acquisition of this data for calculation of the hemodynamic
performance, in other words of the ejected blood volume and, by
relating it to the rhythm, of the heart rhythm. Preferably, the
hemodynamic sensors 5 comprise an intramyocardial pressure sensor
situated close to an intraventricular detection and stimulation
electrode belonging to the means 1. The means 6 are sensitive to
the pressure amplitude detected by the pressure sensor and check
whether this amplitude varies just after the rise in pressure, so
as to determine the zone MMRZ. The values originating from the
means 6 are sent to comparison means 7 in which there is also
stored either a threshold above which the hemodynamics are to be
maintained or a hemodynamic optimum which will have been recorded,
for example beforehand, by the device according to the invention.
These means 7 send the result of their calculation to means 8 which
also receive information relating to the refractory period
originating from the means 4 and to the characteristics of the
electrocardiogram, in particular the rhythm originating from the
means 3. The coupling, in other words the interval provided between
the last wave R which has just been detected and the transmission
of the stimulation or of the stimulating burst of pulses, is
determined in the logic means 8. These means can also modify not
only the coupling interval, if necessary, but also other
characteristics such as the duration of the burst, the number of
pulses, the pulse interval or else the intensity or duration of
each of the pulses, as a function of the information received.
[0344] The means 8 control the means 9 for generating a burst of
pulses.
[0345] The means for comparison 7 as a function of the degree of
efficacy of the observed hemodynamics and its comparison with the
desired values can also optionally modify the frequency of the
stimulations by means 10 which control the pulse generator 9, for
example in particular when the spontaneous electrogenesis of the
patient is inadequate to cause a suitable heart rhythm.
[0346] The device can also comprise metabolic sensors 11, for
example sensors of local oxygen saturation pressure or of its
equivalent in concentration of transmembrane or free electrons as
measurable by an oxydo-reduction co-efficient within a vein of the
coronary sinus and, for example, relating to the right
intra-auricular venous blood and the left intra-auricular arterial
blood and/or CO.sub.2 and/or pH etc. sensors connected to
acquisition means 12 determining a value such as the O.sub.2
consumption acquired for a comparison in means 13 with one or more
programmed or previously stored thresholds. A logic means 14 which
influences the means 10 (or in a simpler case, the means 8) can
thus be employed in order to modify, if necessary, the parameters
or the coupling of the burst or other variations provided in the
means 10.
[0347] The device in FIG. 6 has means identical to that described
in FIG. 5 and additional features. The means 6 is thus arranged so
as to be able to identify the zones MMRZ in duration and geometric
position relative to the zones RZ and RNZ.
[0348] The means for comparison with already stored optimum series
can be arranged so as to store dangerous critical sequences which
have already existed or have been entered by programming and allow
an action if a sequence of cycles which is considered to be
critical is detected in order, for example, to act on a
defibrillation means or to stop operation of the device according
to the invention and to cause it to operate in the manner of a
conventional orthorhythmic pacemaker or VVI or DDD.
[0349] The means 3 is also arranged so as to also acquire the
intervals R--R' directly.
[0350] Finally, an additional means 15 is provided to receive
information from the means 4, these means 4 being arranged so as to
acquire information also on the arrhythmias, said means 15 thus
allowing the detection and selection of arrhythmias, preferably the
distinction between spontaneous arrhythmias and those induced by
the device, said means 15 retroacting on the means 10 which
controls the transmission of the pulses.
[0351] During echocardiography, the OIST at rest allows a basal CC
to be immediately followed by one or more CC with maximum
contractility or vice versa and enables their quantitative and
geometric difference to be measured. For a progressive effort test,
however, it would be necessary to use conventional means. The
comparison between maximum contractility of the OIST and that
obtained by physical effort or substances of the dopamine,
noradrenaline, etc. type could give new indications of myocardial
function.
[0352] The automatic measurement of the variations of the
refractory zones ERZ and MRZ during the effort tests, in particular
under echocardiographic control, provides information on an
intracellular myocardial state.
[0353] In the case of functional resynchronizing bi-ventricular
cardiac stimulation used, for example, in the case of a blockage of
the left branch, grave hypertrophy of the myocardium etc., the
hemodynamic result can basically be further improved by adding a
OIST which is controlled by the bi-ventricular stimulator which
will reinforce the intrinsic contractility of each ventricle and
lead to genetic regeneration which will be observed in the region
of the myocardiums subjected to prolonged intensive physical
training with peripheral muscle exercises.
[0354] An automatic OIST according to the invention comprises a
device for assuring optimum hemodynamics within adjustable limits,
for example of rhythm, pressures: max., min., differential, of
dimensional variations of the contraction, local and general oxygen
saturations (preferably in the coronary sinus and the arterial and
venous blood), of regular continuity of the OIST, etc. In order to
be able to carry out this development, a specially programmed
display should be provided, for example (FIG. 3) in the region of
an oscilloscope having a plurality of simultaneous channels and
while using known signal processing and algorithms, which
comprises, for example, the following parameters in real time:
[0355] an ECG curve showing 3 to 5 cycles with rapid
development,
[0356] the marking of spots (spikes) for detections and
stimulations in the region of the electrodes on a line,
[0357] a curve showing the preferably monopolar intracardial ECG,
for example on a tripolar probe, stimulation being carried out in
bipolar mode which allows the pulse of a burst which effectively
caused the propagated electrical depolarization to be determined
thus allowing the automatic measurement of the ERZs and the
variations thereof during each CC, these measurements being made
possible by the orthorhythmic pacemaker, even in the cause of
auricular fibrillation (K. Theissen, F. Zacouto, Klin. Wschr. 52,
1082-1048, 1974, Germany, Springer-Verlag),
[0358] a curve showing the mechanical curves, variations in
pressures, volumes and acceleration,
[0359] a curve showing the consumption of oxygen or an equivalent
if possible for each or a few cycles such as, for example, venous
and arterial coronary oxygen saturations and their difference
and/or a local arterio-venous oxydo-reduction co-efficient, etc.,
which can preventively alert, prior to hypoxia, of any
over-consumption of oxygen by the myocardium which is manifested,
for example, firstly by an extra membrane accumulation of
electrons.
[0360] The OIST stimulating device can be combined with all
categories of implantable automatic cardiac stimulators AID, and
also, in particular, automatic anti-tachycardic defibrillators,
VVI, DDD, DDDR, etc.
[0361] Reference will be made to FIG. 7 to 9 by way of example.
[0362] In this example, the practitioner or the device according to
the invention notes that a patient suffering from a massive heart
failure has a non-accelerated spontaneous heart rhythm, for example
of less than 125 p/min and, for example, preferably less than 100
p/min.
[0363] Line 1 in FIG. 7 shows the regular rhythm of the waves R (of
the complexes QRS) of this patient, ERZ representing the electrical
refractory zone determined, for example, by one of the means
described in the present invention.
[0364] Line 2 shows the mechanogram detected in response. The
mechanical refractory period MRZ as well as the mechanical diastole
D has also been shown on this curve.
[0365] The electrocardiographic simulation of isotropic stimulation
according to the invention, in which a coupled burst is transmitted
immediately at the instant of the end of the electrical refractory
zone ERZ is shown on line 3, and the extension of the refractory
zone following the complex R' induced by the simultaneous coupled
stimulation can be seen. In this simulation, the data processing
means of the device have anticipated that the base rhythm is barely
modified by simulated inotropic stimulation and the spontaneous
complexes R therefore occur as they did in the absence of
stimulation.
[0366] Line 4 shows the estimated increase, in duration and
intensity of the mechanogram, the increase being immediately
observed as from the second spontaneous wave R, in other words the
first to follow inotropic stimulation R'.
[0367] A reduction in the mechanical diastolic duration D', which
is less than D also results.
[0368] The actual inotropic stimulation of the heart is thus
carried out as provided on the simulation curve 2 in FIG. 7, and it
is checked that an increase in hemodynamic performance is obtained
immediately after the successive first cycle, as in line 4. This
check is continued for a specific duration or a specific number of
cardiac cycles, for example corresponding to one or a plurality of
tens or about one hundred cycles, bearing in mind that a
progressive supplementary increase extending over tens or hundreds
of successive cycles should normally be obtained after the
immediate increase in performance during the second cycle.
[0369] The effect obtained by inotropic stimulation according to
the invention can also be simulated in the same patient on the
basis of the fasted rhythm imposed by the stimulating pulses R3
which prevent the occurrence of the spontaneous signals R (the
suppressed complexes QRS are represented by R2). The line 5 shows
the electrocardiogram corresponding to this simulation with
coupling of bursts and electrical capturing of the heart.
[0370] The line 6 represents the estimated increase in the
mechanogram owing to this simulation. Owing to the comparison means
of the device, the effects of the stimulations in lines 2 and 6 can
thus be compared and, for example, in the case where it would be
estimated that the increase in hemodynamic performance originating
from a mere coupled stimulation according to line 3 is inadequate,
the implementation of a stimulation according to line 5 could be
proposed if the increase and the desired mode is greater and allows
an acceptable increase in cardiac performance to be obtained, for
example a doubling relative to the spontaneous heart rhythm as
estimated in line 2.
[0371] Once the choice of simulation has been made, the device
effectively proceeds with inotroptic stimulation according to line
3, as described hereinbefore or according to line 5 as a function
of the choice made, and the means for acquisition of the
hemodynamics and/or the oxygen consumption thus allow the existence
and extent of the increase in hemodynamic performance to be checked
and compared with the simulated increase.
[0372] In the absence of the increase in the hemodynamic
performance, for example during the two first coupled or paired
stimulating cycles, the device stops inotropic stimulation.
[0373] On the other hand, if a hemodynamic increase is observed,
stimulation is continued, preferably over several tens or one or
more hundreds of cycles. The hemodynamic performance obtained is
thus compared with this result of simulation. If the performance
obtained is comparable to the target performance, for example in a
range of 15% of the target performance, inotroptic stimulation is
continued. If the increase in performance obtained greatly exceeds
the simulated increase, the device can optionally reduce the
performance, for example by allowing for a cardiac stress index CSI
and comparing the performance index CPI and stress index CSI, as
described in the patent U.S. Pat. No. 5,213,098 incorporated here
by reference, and the inotropic simulation can optionally be
performed only for a reduced proportion of cycles. On the other
hand, the observed performance is far less than that estimated to
be necessary and anticipated by the simulation, the device can stop
inotropic simulation.
[0374] Referring to FIG. 8 there is shown a case of cardiac failure
associated with a spontaneous tachycardial rhythm, for example
greater than 125 cycles per minute. The last spontaneous cycle R is
shown together with the corresponding hemodynamic performance in
line 2.
[0375] In such a case, the device simulates the transmission of a
stimulating burst toward the end of the refractory period of the
last spontaneous signal R and this extends the refractory period of
the heart so that the following complex QRS which will be produced
at instant R2 owing to the tachycardia can no longer be produced
and this causes the occurrence of a retarded spontaneous complex
R3. The coupling stimulating burst R4 is thus continued and it can
be seen that by preventing the occurrence of the spontaneous
tachycardic complex R2 each time, a lower rhythm, for example
divided by two, is finally obtained.
[0376] Usually however, it is preferable to carry out complete
electrical management of the heart; the spontaneous complex R3 is
thus replaced by stimulation at a slightly faster rhythm.
[0377] Increased simulated hemodynamic performance normally
corresponds to this stabilized normal rhythm because the EPR (PESP)
effect largely over-compensates the reduction in the number of
contractions per minute.
[0378] If this simulation promises adequate hemodynamic
performance, inotropic stimulation according to the procedure in
line 1 of FIG. 8 is actually carried out and, as mentioned
hereinbefore, the response and amplitude of the response obtained
is checked for one, two or three cycles then for a greater number
of cycles. In such an embodiment, a stimulating pulse can be
transmitted at a higher rhythm if the simulated or actually
obtained hemodynamic performance is inadequate.
[0379] FIG. 9 shows the electrocardiogram and the corresponding
mechanogram of a patient. The electrocardiogram shown is line 1
shows the complexes QRS and, more precisely, the wave R which is
spontaneous or stimulated at a base rhythm, for example of 60
pulsations/min. The appearance of the complex QRS creates an
electrical refractory zone ERZ which ends more or less with the
wave T without an adequate correlation generally being able to be
established. This refractory zone is followed by the electrically
sensitive diastole ELD.
[0380] Line 2 shows that the increase in pressure of the
mechanogram takes place after an electromechanical coupling period
EM, hereinafter also called E. An isovolumetric contraction first
occurs when the valves are not open, for period Cl. This
contraction is followed a contraction with blood ejection EJ
between the opening A of the aortic valve and the opening M of the
mitral valve. DE represents the mechanical diastole, which is
firstly a motor diastole and then elastic and passive for
filling.
[0381] The maximum mechanical refractory zone during which the
cardiac muscle is in the most contracted state is represented by
MMRZ. This zone, which corresponds to the peak of the pressure
curve is relatively flattened in the illustrated example because
the pressure curve has been obtained by a sensor which measures the
intracavitary blood pressure within the ventricle. When an
intramyocardial pressure sensor is placed in a local region or
zone, however, the rise in local pressure is very pronounced and
allows the local maximum mechanical refractory zone close to the
active electrode to be distinguished easily.
[0382] In an embodiment of the present invention, the
electrocardiogram of line 1 is acquired in this local region, for
example preferably the myocardial region adjacent to the
ventricular stimulation and detection electrode, and the
intramyocardial pressure is also acquired in this myocardial
region. It is reasoned hereinafter as if the curves of lines 1 and
2 in FIG. 9 represented local curves in the selected region.
[0383] It is thus observed that the electrical refractory zone can
partially or even completely overlap the zone MMRZ. If the
superimposition is partial, an effective critical zone ECZ to be
targeted, which may be equal to the zone MMR if the electrical
refractory zone ERZ ends before the beginning of the zone MMRZ and
may be zero is ERZ is elongated and encompasses the duration of the
zone MMRZ is defined between the zone ERZ and the end of the zone
MMRZ.
[0384] According to a particularly preferred embodiment of the
invention, the coupled or paired stimulation is transmitted during
the zone ECZ. This may quite frequently be approximately 30 to 40
ms and, in this case, the sufficiently early transmission toward
the end of ERZ of a burst of pulses having a pulse interval, for
example of 20 ms, will certainly cause a stimulation in the
targeted zone ECZ without a detrimental increase in the local
oxygen consumption, this stimulation producing the
post-extrasystolic potentiation expected with the slightest
increase in oxygen consumption relative to the increase in
mechanical work by the myocardium PESP.
[0385] If the zone ECZ tends to shrink, the device could thus
advantageously reduce the interval between the pulses of the burst
so as to guarantee that a pulse of the burst will fall in this zone
ECZ. However, it is preferable not to shrink the duration between
two successive pulses substantially below 10 ms, the electronic
means not allowing the stimulating pulse of the burst to be
identified in this case.
[0386] Consequently, if the zone ECZ is less than 10 or 15 ms, it
is preferable not to transmit paired or coupled pulses.
[0387] The same applies if it observed over a specific number of
cycles that the zone ECZ varies too anarchically in duration or
time.
[0388] In a particularly advantageous embodiment, the zone ERZ will
be detected by using pulse trains as described hereinbefore, and
the positions and durations of the zones ECZ of a plurality of
cycles, for example from 30 to 3000 cycles, will be stored for
detecting whether the zone ECZ is almost stable or whether it has a
tendency to decrease or increase and an intervention could thus be
made, this time by transmitting a stimulating pulse, preferably
rather toward the estimated end of the zone MMRZ of the current
cycle, assuming that the zone ECZ exists at this instant.
[0389] Owing to this storage and checking which could be carried
out by the analyzing simulator ASIM according to the invention, it
could be brought about that only a small number and even no pulse
causing electrical depolarization occurs outside the zone MMRZ,
thus allowing the local oxygen consumption caused by the inotropic
paired or coupled stimulation to be limited. By suitably selecting
the place in the heart where the intramyocardial pressure and the
electrical depolarization are detected and by stimulating in or in
the vicinity of this location, the intramyocardial propagation of
the depolarization, caused by the inotropic stimulation, could be
made to take place in concordance with the continuous propagation
of a strong contraction, in particular a maximum myocardial
contraction in the new territories where stimulation depolarization
is propagated, so that the oxygen consumption resulting from the
paired or coupled stimulation will also remain limited in a large
portion or even all of the ventricular myocardium. For this
purpose, it is preferable to detect the zone MMRZ in an initial
myocardial zone where the propagation of depolarization begins, the
electrical influx thus being propagated in the remainder of the
myocardium at the same time and at a speed substantially equal to
the maximum contraction, the coupling thereof remaining
sufficiently constant.
[0390] In certain particular cases, for example if a change in the
operation of the intramyocardial bundles of conduction has been
detected, for example in the case of pathological blocks of branch
or local zones, the zone MMRZ and optionally the corresponding
electrical depolarization signals could be detected in a plurality
of locations and stimulated in these locations during their
respective zones MMRZ or more precisely ECZ.
[0391] FIG. 10 shows the increase in the simulated hemodynamic
efficacy over three spontaneous cycles in a patient.
[0392] Line 1 represents the spontaneous rhythm, for example of 90
p/mm in a patient suffering from acute cardiac failure.
[0393] Line 2 shows the spontaneous variation in pressure in the
left ventricle generated by the spontaneous rhythm.
[0394] Line 3 shows the electrogram of a paired stimulation
simulated in this same patient, which maintains a rhythm identical
or similar to that in line 1.
[0395] Line 4 shows the resultant simulated variation in left
intraventricular pressure.
[0396] Line 5 consists of a superimposition of the actual pressure
differences in line 2 and simulated pressure differences in line 4,
the differences being hatched. It can be seen, in particular, that
the initial gradient of increase in systemic pressure
.DELTA.p/.DELTA.t increases by 25% and the diastolic
.DELTA.p/.DELTA.t, in other words of reduction in pressure, by more
than 30%.
[0397] The flow per systole is increased by 35% and the flow per
minute by 33%.
[0398] The duration E of electromechanical coupling is reduced by
30%.
[0399] The analysis of this simulation shows a significant increase
in hemodynamics.
[0400] FIG. 11 shows the control panel of a device ASIM according
to the invention, divided into three parts 1001, 102, 103.
[0401] The panel 101 comprises a subpanel for auricular control 104
corresponding to the auricular stimulation and detection electrodes
and a ventricular subpanel 105 corresponding to ventricular
stimulation and detection electrodes. The panel 104 has three
control buttons, namely 108 for selecting the amplitude of the
stimulating pulses, 109 for the sensitivity of detection and 110
for the duration between the auricular and ventricular
stimulations, if the mode DDD is selected. The ventricular panel
105 comprises three buttons 111, 112, 113 for the adjustment and
amplitude of the ventricular pulses, the sensitivity of the
ventricular detection electrode and the auriculo-ventricular
offset. The button 114 allows the orthorhythmic stimulation rhythm
to be defined. The button 106 allows the stimulation to be carried
out or interrupted and the button 107 allows a passage to
auricular, ventricular or DDD mode.
[0402] The panel 102 comprises stimulation control buttons OIST
according to the invention. The button 115 allows the stimulation
OIST to be carried out or interrupted and the button 116 allows
automatic stimulation to be triggered only for a single cycle.
[0403] The subpanel 117 has a set of buttons, namely 118 for
coupling (as a percentage), 119 for coupling in fixed ms, 120 for
displaying the base stimulation period.
[0404] The subpanel 121 allows the proportion of cycles to be
stimulated to be selected.
[0405] The subpanel 124 has three buttons 125, 126 and 127 for
defining the parameters of the pulses of the burst of inotropic
stimulating pulses, namely the number of pulses in the burst by the
button 125, the interval between the two successive pulses in the
burst by the buttons 126 and the amplitude of the pulse of the
burst (button 127).
[0406] The emergency stop button 128 allows the immediate stoppage
of inotropic stimulation.
[0407] The lower portion 103 allows the simulation ASIM according
to the invention to be displayed and adjusted and allows the
simulation to be compared with the initially detected parameters by
optionally actuating the portion 101 and with parameters
originating from the actuation of an OIST by the panel 102.
[0408] The portion 103 comprises a screen 128 on which the
electrical and real and simulated mechanical curves and the
juxtaposition thereof appear as shown in FIG. 10.
[0409] A subpanel 130 displays the spontaneous values detected
(spont), corresponding simulated values (simu) and the comparisons
thereof as a percentage of spontaneous value, for the parameters
diastolic .DELTA.p/At, systolic ventricular rate, ventricular rate
per minute and electromechanical coupling value E of the
ventricle.
EXAMPLES
[0410] The following examples are intended as illustrative and not
limiting as to various embodiments of the present invention, slight
modification and/or addition to these Examples is intended to be
expressly covered hereby. [0411] 1. Device for stimulating and/or
potentiating the heart muscle and/or the myocardial cells, allowing
a significant increase in the hemodynamic performance of the heart
and/or the treatment of tachycardia, tachyarrhythmia or auricular
fibrillation, comprising: [0412] means for the automatic
acquisition (1, 2, 3) of the heart rhythm and optionally of its
origin, for detecting, in particular, the interval between at least
the last two waves R (induced or spontaneous) of the cardiac cycle
just completed, [0413] means for the precise acquisition of cardiac
hemodynamics, [0414] means (4) for determining, continually or
periodically, in real time, the duration of the electrical
refractory period (ERZ) following the last wave R of said cycle,
[0415] means for evaluating at least one parameter relating to the
functional cell state of the myocardium, [0416] and means (8, 9,
10) which are subordinate to said evaluating means for sending,
substantially without delay at the end of said refractory period
(ERZ), at least one paired or coupled stimulating pulse adapted to
said functional cell state. [0417] 2. Device according to example
1, wherein said evaluating means determine the position and
duration of a critical zone effective in targeting ECZ, which is
placed immediately after the end of the electrical refractory zone
and terminates at the end of a refractory zone of maximum
myocardial contraction MMRZ, the transmission of said stimulating
pulse intervening in said ECZ zone if it is present and targetable.
[0418] 3. Device according to either example 1 or example 2,
wherein said evaluating means detect the excitability threshold of
the myocardium during each cycle or periodically. [0419] 4. Device
according to any one of examples 1 to 3, wherein the means (8, 9,
10) send a burst of stimulating pulses substantially at the end of
said refractory period (ERZ), the duration of the burst and the
pulses repetition interval being such that a stimulating pulse of
the burst is sent to the heart substantially without delay after
the end of said refractory period. [0420] 5. Device according to
example 4, wherein the means (4) for determining the duration of
the electrical refractory period (ERZ) are sensitive without delay
to the detection of the pulse of a burst which triggered a complex
(R'). [0421] 6. Device according to any one of examples 1 to 5,
wherein, even when the device generates a single stimulating pulse
instead of a burst, the means (4) for determining the duration of
the refractory zone are arranged so as to acquire, by scanning a
second pulse, the substantially exact duration of the refractory
zone, this scanning being carried out, for example, during the
preceding or current cardiac cycles. [0422] 7. Device according to
any one of examples 1 to 5, wherein the beginning of the burst of
stimulating pulses is selected so as to begin just before the
estimated end of the refractory period, and the duration of this
burst and consequently the number of stimulating pulses is
advantageously such that at least one stimulating pulse will occur
before and a following pulse very quickly after the end of said
refractory period. [0423] 8. Device according to any one of
examples 1 to 6 comprising means for advancing or retarding the
burst relative to an estimation of the refractory zone and/or
modifying the pulse interval within the burst, the device having
automatic acquisition means, in particular by obtaining the
intracardiac ECG for determining, in particular by processing the
intracardiac electrical signal in the region of the detecting
and/or stimulating electrode, which stimulating pulse in the burst
triggered the wave R' and for functionally modifying the burst.
[0424] 9. Device according to any one of examples 1 to 8,
comprising means which are sensitive to the spontaneous or
stimulated waves R and/or to the determination of the electrical
and mechanical refractory zones, in particular by scanning all of
the burst or only within this burst and/or means for the very rapid
determination of the heart excitability thresholds, for example by
providing stimulating pulses of variable intensity, including
subliminal pulses for allowing the instantaneous measurement
thereof within the burst. [0425] 10. Device according to any one of
examples 1 to 9 comprising anti-tachycardic stimulation means and
extrasystole-sensitive means for automatically stopping said
stimulation on occurrence of excessively great hemodynamic
instability and electrical arrhythmia corresponding to
predetermined criteria. [0426] 11. Device according either example
9 or example 10, comprising, in addition to the rhythm acquisition
means, refractory zone duration determination means and single
pulse or burst transmission means, means (7, 10) which are
sensitive to the precise acquisition of the hemodynamics relative
to the rhythm and its origin in the heart for determining
variations in hemodynamic efficacy, these means being capable of
controlling the transmission and optionally the parameters of the
pulse or the burst, preferably at a rhythm close to that which
produced the most favorable hemodynamics for the patient at a given
moment. [0427] 12. Device according to example 11, wherein said
means act on parameters such as: a programmed ventricular rhythm
and/or an automatic adjustment of the beginning or end or duration
of the burst or the number or the characteristics, in particular
width, interval intensity, polarity of the pulses in the burst, or
else a location of the transmission of the burst at one or more
stimulating electrodes. [0428] 13. Device according to example 12,
comprising means for progressively reducing a burst to a single
pulse or a small number of pulses, in particular by periodically
probing with at least a second pulse which moves progressively
ahead of the stimulating pulse to automatically measure the
beginning of the non-refractory zone so that, when the exploratory
pulse retracts towards the stimulating pulse, the stimulating pulse
can be retarded, in particular periodically in the event of
instability in operation until the beginning of the reduction of
the ventricular pressure/volume curve or increase in the oxygen
consumption and/or a corresponding parameter, in particular the
membrane secretion of electrons, local pH or ketone bodies is
obtained, this position corresponding to the exceeding of the end
of the maximum contraction mechanical refractory zone (MMRZ) [0429]
14. Device according to any one of examples 1 to 13 further
comprising means (11, 12) for acquiring metabolic parameters, in
particular concerning local oxygen consumption and/or equivalents
thereof such as the measurement of the densities of accumulated
electrons, lactic acid, pH or ketone bodies. [0430] 15. Device
according to any one of examples 9 to 14, comprising means for
passing from a paired stimulation to a coupled stimulation, in
other words to an entirely stimulated rhythm, said means being
sensitive to the electrocardiogram and/or hemodynamics and/or
myocardial metabolism acquisition means. [0431] 16. Device
according to any one of examples 1 to 15, for treating isolated
premature arrhythmias and extrasystoles, comprising a plurality of
electrodes disposed at different locations of the heart muscle and
acquisition means which are sensitive to the electrical signals
appearing at the electrodes or remotely for observing, at an early
stage, the occurrence of an electrical extrasystole in a myocardial
zone close to that of the electrodes initially concerned, the
stimulating pulse sending means thus being made sensitive to such
an observation so as to emit, in a nearby electrode or in a
plurality of electrodes, a stimulating pulse or burst of which the
electrical propagation into the myocardium is directed toward the
myocardial zone affected by the extrasystole and causing fusion
between the spontaneous and stimulated depolarizations which blocks
the propagation of the extrasystole. [0432] 17. Device according to
any one of examples 1 to 15 for treating isolated arrhythmia and
extrasystoles, comprising one or more electrodes, in particular
juxta- or extracardial or intracavitary ventricular electrodes, in
particular without exclusive contact with the myocardium, for the
instantaneous detection of a premature extrasystole, said device
being arranged so as to instantaneously trigger, if said
extrasystole is detected, the stimulation by a pulse or by a burst
of pulses from all the available stimulating electrodes, thus
creating a fusion complex between the propagations of the
stimulated and extrasystolic depolarizations. [0433] 18. Device
according to any one of examples 1 to 17, comprising means for
rapidly detecting an extrasystole, the means of the device being
sensitive to the acquisition of this extrasystole for reducing or
even eliminating, preferably temporarily, the electrical diastolic
phases (D), in particular either by increasing the stimulation
rhythm in the heart with electrical control of the device or by
taking the control to send a stimulating pulse at the very
beginning of the electrical diastole. [0434] 19. Device according
to any one of examples 1 to 18 comprising means for increasing,
should an arrhythmia corresponding to predetermined criteria occur,
the number and/or intensity of the pulses of the burst to
potentiate the effect of stabilization on the myocardial cell
membranes. [0435] 20. Device according to any one of examples 1 to
19, comprising means for reducing, in the event of arrhythmia, the
intensity of the pulses of the burst, the device thus monitoring
whether arrhythmia continues. [0436] 21. Device according to any
one of examples 1 to 20, arranged so as to acquire a cardiac
mechanogram, in particular until the occurrence of a cycle which is
sufficiently long to obtain a good myocardial contraction, the
stimulating means being arranged so as to transmit a stimulating
pulse or burst only at the peak of the mechanical contraction
(MMRZ) located within the plateau of the mechanogram curve, in
particular just before the end of the electrical refractory zone
(ERZ), after which the device stimulates, immediately after the end
of the electrical refractory zone which has just been extended,
thus canceling the electrical diastole. [0437] 22. Device for
stimulating and/or potentiating the heart muscle and/or the
myocardial cells, for significantly increasing the hemodynamic
performance of the heart and/or the treatment of auricular
tachycardia, tachyarrhythmia or fibrillation comprising: [0438]
means for the precise acquisition of the cardiac hemodynamics (5,
6) and comprising a means for instantaneous detection of the
maximum myocardial refractory zone (MMRZ) at a precise location of
the myocardium, [0439] and means for sending at least one
stimulating pulse and preferably a burst of stimulating pulses from
the local region in which the occurrence of the zone MMRZ is
detected. [0440] 23. Device according to example 22 comprising
means for automatic acquisition (1, 2, 3) of the heart rhythm and
optionally of its origin, in particular for obtaining the interval
between at least the last two waves R (induced or spontaneous) of
the cardiac cycle which has just been completed and means (4) for
determining continually in real time the duration of the electrical
refractory period (ERZ) following the last wave R of a cardiac
cycle, said device being arranged so as to detect whether an
electrical depolarization signal has been produced by said
stimulation in said zone MMRZ. [0441] 24. Device according to any
one of examples 22 and 23, comprising means for detecting and
storing the duration of said maximum myocardial refractory zone
(MMRZ) and sending said local stimulating pulse or burst of
stimulating pulses after a short duration after the beginning, in
the current cycle, of the beginning of said zone MMRZ and before
the estimated end of said zone by storing said duration in the
preceding cycles. [0442] 25. Device according to any one of
examples 2 to 24 wherein the stimulating pulse or at least one
stimulating pulse of a burst falls in said zone (MMRZ),
substantially at the location of the myocardium where the
occurrence of said zone (MMRZ) is detected. [0443] 26. Device
according to any one of examples 1 to 25 comprising implanted means
for measuring intracavitary pressure and capable of detecting a
zone of maximum pressure in the plateau of the cardiac mechanogram
and to which said means for transmitting a stimulating pulse or
burst are sensitive. [0444] 27. Device according to any one of
examples 1 to 25 comprising at least one sensor for detecting
intramyocardial pressure. [0445] 28. Device according to example
27, wherein said intramyocardial pressure sensor is located in the
intra-auricular septum and/or in a free cardiac or intraventricular
wall. [0446] 29. Device according to any one of examples 1 to 25
comprising means for measuring the variation in the volume of the
heart or a portion of the heart, detecting and storing the interval
of the cycle where said volume has reached and maintained its
minimum value, said means for sending a stimulating pulse or burst
being sensitive to said measuring means. [0447] 30. Device
according to any one of examples 2 to 29 comprising means for
detecting the oxygen consumption of the heart and/or an equivalent,
in particular the local pH or concentration of ketone bodies and
means for detecting the zone of maximum cardiac contraction (MMRZ)
by estimation by detecting, during one or more previous cycles, the
relative position in the cycle and/or in the mechanogram of the
pulse or the pulse of a burst which has generated a
post-extrasystolic potentiation (PESP) with minimal oxygen
consumption relative to the measured blood flow per minute. [0448]
31. Device according to any one of examples 2 to 30 comprising
[0449] means for continuously measuring electrical refractory zones
ERZ in a location of the heart, [0450] means disposed substantially
in the heart region for precisely measuring the zones of maximum
myocardial contraction MMRZ, [0451] the device being arranged so as
to acquire, from said means, the temporal superimposition, in the
same cycle, of said zones ERZ and MMRZ and determine the common
zone known as the critical zone ECZ. [0452] 32. Device according to
example 31, wherein means are arranged so as to immediately send at
least one stimulating pulse into said region of the heart, during
said zone ECZ. [0453] 33. Device according to example 32, wherein
said means for checking the temporal superimposition are sensitive
to a shift between the zones ERZ and MMRZ in order to send a
stimulating pulse or burst supplying at least one pulse to the
interior of the zone ECZ.
[0454] 34. Device according to example 33 wherein said sensitive
means allow the time interval between two pulses of a burst to be
reduced so as to increase the probability of having a pulse during
said zone ECZ. [0455] 35. Device according to example 34, wherein
the duration between two pulses of a burst cannot be reduced to
less than a value of approximately 10 ms. [0456] 36. Device
according to any one of examples 31 to 35 wherein, if it is
impossible to cause at least one pulse to travel to the interior of
the zone ECZ, the device stops the coupled or paired stimulation.
[0457] 37. Device according to any one of examples 2 to 36, wherein
the occurrences and time durations of the zones ECZ are stored
during a plurality of cycles and the development thereof is
analyzed in order to anticipate any tendency to the suppression of
said zone ECZ and, in this case, to implement a treatment, in
particular by perfusion of drugs or change of the OIST rhythm in
order to act on the duration of the zones ERZ or MMRZ or the
overlap thereof. [0458] 38. Device according to any one of examples
1 to 37 comprising: [0459] means for acquiring information relating
to a patient's electrocardiogram, including the heart rhythm,
[0460] means for acquiring information relating to the patient's
hemodynamic performance, [0461] analysis means which are sensitive
to said acquisition means for stimulating the effect of inotropic
paired or coupled stimulation adapted to the patient's heart.
[0462] 39. Device according to example 38, further comprising means
for automatically comparing said acquired information relating to
the patient's hemodynamic performance with the simulated effect on
said performance of an inotropic paired stimulation. [0463] 40.
Device according to any one of examples 38 and 39, wherein said
acquisition and comparison means allow the acquisition and
comparison of the information cycle by cycle. [0464] 41. Device
according to any one of examples 38 to 40, wherein said means for
collecting information relating to the patient's hemodynamic
performance measure at least one of the following parameters
relating to the cardiac contraction: [0465] gradient (dp/dt) of the
phases of ascent and/or descent of the intracavitary and/or
intramyocardial pressure; [0466] duration of the systolic pressure
plateau, corresponding to systolic ejection; [0467] duration of the
systole (cardiac contraction); [0468] duration of the diastole
(fast and slow active motor filling phases); [0469] ratio of
diastole and systole durations; [0470] quality of the diastole, in
particular filling depression; [0471] electromechanical coupling
(period separating the beginning of a QRS complex from the
beginning of the mechanical systole which it causes); [0472] shift
between the intramyocardial contraction curve close to the local
detecting electrode and the global intracavitary contraction curve.
[0473] 42. Device according to any one of examples 38 to 41,
comprising means for comparing information relating to the
electrocardiogram and to the hemodynamic performance of a
simulation of inotropic paired or coupled stimulation with
corresponding information acquired during a subsequent identical or
similar actual inotropic stimulation. [0474] 43. Device according
to any one of examples 38 to 42, comprising means for acquiring or
calculating a threshold level of values of the information on the
simulated hemodynamic performance adapted to the patient and, if
the threshold is exceeded, causing an identical or similar
inotropic paired or coupled actual stimulation. [0475] 44. Device
according to any one of examples 38 to 43, wherein said means for
acquiring the information relating to the patient's
electrocardiogram and to the patient's hemodynamic performance are
arranged so as to acquire this information at different rhythms.
[0476] 45. Device according to example 44, arranged so as to
temporarily impose, on the patient's heart, rhythms which vary in
increments or progressively and during which said information
relating to the electrocardiogram and said information relating to
the corresponding hemodynamic performance are acquired. [0477] 46.
Device according to any one of examples 38 to 45, wherein said
means sensitive to the acquisition means are arranged so as to
simulate the effect of a plurality of inotropic paired or coupled
stimulations at different heart rhythms. [0478] 47. Device
according to any one of examples 38 to 46, arranged so as to carry
out said comparison during a limited number of cycles of the actual
inotropic stimulation and, if the absence of a satisfactory level
of hemodynamic performance is observed, to terminate the current
stimulation. [0479] 48. Device according to example 47 wherein said
number of cycles is approximately 10 or less, in particular 1, 2 or
3 cycles. [0480] 49. Device according to any one of examples 47 and
48, arranged so as, if an adequate increase in initial hemodynamic
performance is observed, to continue the inotropic stimulation and
to detect and store whether the increase in initial hemodynamic
performance is maintained and/or further increases progressively
for a greater number of cycles. [0481] 50. Device according to
example 49, wherein said greater number of cycles is at least about
100 cycles. [0482] 51. Device according to any one examples 38 to
50, wherein said analysis means are arranged so as to include the
medicinal inotropic effects likely to interfere with the effect of
electrical inotropic stimulation. [0483] 52. Device according to
any one of examples 38 to 51, comprising means for emphasizing,
visually and/or quantitatively by calculation, the differences
between the curves for the simulation and for the corresponding
actual stimulation. [0484] 53. Use of a device according to any one
of examples 1 to 52 for the production of a device for treating
acute or severe heart failure. [0485] 54. Use of a device according
to any one of examples 1 to 52 for preparing an assembly intended
for carrying out a process for cardiac regeneration comprising the
following steps: [0486] implanting in the heart, in particular in a
right or left atrium and/or a right or left ventricle, regeneration
cells, in particular in the sub-endocardial or intramyocardial
position, in particular in a plurality of encapsulated groups of
cells or in a cell blanket or cell mesh, [0487] and carrying out
stimulation according to the invention, preferably paired
stimulation. [0488] 55. Process for stimulating the heart muscle to
allow a significant increase in hemodynamic performance of the
heart and/or the treatment of tachycardia comprising the following
steps: [0489] providing a permanently implanted heart stimulation
device and, with the aid of this device, [0490] automatically
acquiring the heart rhythm so as to obtain, in particular, the
interval between at least the last two waves R (induced or
spontaneous) of the just completed cardiac cycle, [0491]
determining in real time, in particular on request, preferably
continually, the duration of the electrical refractory period (ERZ)
following the last wave R of said cycle, [0492] and sending at
least one stimulating pulse substantially without delay at the end
of said refractory period (ERZ). [0493] 56. Process according to
example 55, wherein there are used means (4) for determining the
duration of the electrical refractory period (ERZ), which are
sensitive to the detection of that pulse in a burst which has
triggered a complex R', and means for determining the maximum
mechanical refractory zone MMRZ, and a zone ECZ posterior to the
electrical refractory zone ECZ is determined in said zone MMRZ and,
if said zone ECZ exists, at least one stimulating pulse is sent
into said zone ECZ. [0494] 57. Process according to either example
55 or example 56, even when the device generates a single
stimulating pulse instead of a burst, wherein the substantially
exact duration of the refractory zone is acquired, for example by
scanning of a second pulse, this scanning being carried out, for
example, during the preceding cardiac cycles or the current cycle.
[0495] 58. Process according to either example 55 or example 56,
wherein the beginning of the burst of stimulating pulses is
selected so as to begin just before the estimated end of the
refractory period, and the duration of this burst and consequently
the number of stimulating pulses is advantageously such that at
least one stimulating pulse will occur before and a following pulse
very quickly after the end of said refractory period. [0496] 59.
Process according to any one of examples 55 to 58, wherein there
are used means for advancing or retarding the occurrence of the
burst relative to an estimation of the refractory zone and/or
modifying the pulse interval within the burst, the device having
automatic acquisition means, in particular by obtaining the
intracardiac ECG for determining, in particular by processing the
intracardiac electrical signal in the region of the detecting
and/or stimulating electrode, which stimulating pulse in the burst
triggered the wave R', and thus obtaining the electrical refractory
zone (ERZ) and functionally modifying the burst. [0497] 60. Process
according to any one of examples 55 to 59, wherein there are used
means which are sensitive the spontaneous or stimulated waves R
and/or to the determination of the electrical and/or mechanical
refractory zones, in particular by scanning all of the burst or
only within this burst and/or means for the instantaneous
determination of the heart excitability thresholds, for example by
providing stimulating pulses of variable intensity, including
subliminal pulses for allowing the measurement thereof within the
burst. [0498] 61. Process according to any one of examples 55 to
60, wherein there are used anti-tachycardic stimulation means and
extrasystole-sensitive means for automatically stopping said
stimulation on the occurrence of excessive hemodynamic instability
and electrical arrhythmia corresponding to preselected criteria.
[0499] 62. Process according to any one of examples 55 to 61,
wherein precisely measured cardiac hemodynamic (5, 6) information
is further acquired. [0500] 63. Process according to example 62,
wherein there are used one or more intracardiac pressure sensors or
such sensors disposed in the proximity of the heart and sensors for
determining variations in heart volume, for example electrical
impedance or echographic sensors. [0501] 64. Process according to
either example 62 or example 63, wherein, in addition to the rhythm
acquisition means, means for determining the duration of refractory
zone and means for transmitting a pulse or a burst, there are used
means (7, 10) which are sensitive to the precise acquisition of the
hemodynamics for determining the variations in efficacy of the
hemodynamics, these means being capable of controlling the
transmission and optionally the parameters of the pulse or the
burst, preferably in a manner resembling that which produced the
hemodynamics which are most favorable for the patient at a given
moment. [0502] 65. Process according to example 64, wherein said
means act on parameters such as: a programmed ventricular rhythm
and/or an automatic adjustment of the beginning or end or duration
of the burst or the number or the characteristics, in particular
width, intensity, polarity, density, interval of the pulses in the
burst, or else a location of the transmission of the burst at one
or more stimulating electrodes. [0503] 66. Process according to any
one of examples 55 to 65, wherein there are used means for
progressively reducing a burst to a single pulse, in particular by
probing periodically with at least a second pulse which travels
progressively ahead of the stimulating pulse so as to automatically
measure the beginning of the non-refractory zone in such a way
that, when the exploratory pulse retracts toward he stimulating
pulse, this pulse itself can be retracted, in particular
periodically in the event of operational instability, until the
beginning of reduction of the precise ventricular pressure/volume
curve or increase in the oxygen consumption or in blood acidosis
(pH) or in myocardial membrane secretion of electrons, this
position being able to correspond to the exceeding of the end of
the mechanical refractory zone with maximum active contraction
(MMRZ). [0504] 67. Process according to any one of examples 55 to
66, wherein there are acquired metabolic parameters, in particular
of oxygen consumption and/or equivalents thereof such as the
measurement of electron densities of myocardial cell membrane or
increase in ketone bodies, lactic acid, etc. [0505] 68. Process
according to any one of examples 55 to 67, wherein there are used
means for passing from paired stimulation to coupled stimulation,
said means being sensitive to the means for acquiring the
electrocardiogram and/or the hemodynamics and/or the myocardial
metabolism. [0506] 69. Process according to any one of examples 55
to 68, for treating isolated arrhythmia and extrasystoles, wherein
a plurality of electrodes disposed at different locations of the
heart muscle are implanted and, with acquisition means which are
sensitive to the electrical signals appearing at the electrodes,
the local occurrence of an electrical extrasystole in a myocardial
zone is observed at an early stage, the stimulating pulse
transmission means thus being made sensitive to such an observation
so as to instantaneously emit in a nearby electrode or in a
plurality of electrodes, a stimulating pulse or burst of which the
electrical propagation into the myocardium is directed toward the
myocardial zone affected by the extrasystole so as to lead to a
fusion complex between the stimulated and extrasystolic
depolarization which blocks the propagation of the extrasystole.
[0507] 70. Process according to any one of examples 55 to 69
wherein, if an extrasystole is detected quickly, the electrical
diastolic phases (D) are reduced or eliminated, preferably
temporarily, in particular either by increasing the stimulation
rhythm in a heart with electrical control of the device or by
taking the control so as to send a stimulating pulse at the very
beginning of the electrical diastole. [0508] 71. Process according
to any one of examples 55 to 70 wherein, if an arrhythmia
corresponding to preselected criteria occurs, the number and/or
intensity of the pulses of the burst are increased to potentiate
the effect of stabilization of the myocardial cell membranes,
subject to the simultaneous observation of maintenance of
electrical and hemodynamic tolerance. [0509] 72. Process according
to any one of examples 55 to 71, wherein there are used means for .
. . and reducing, in the event of arrhythmia corresponding to
preselected criteria, the intensity of the pulses of the burst, the
device thus monitoring whether the arrhythmia continues or
improves.
[0510] 73. Process for inotropic cardiac stimulation according to
any one of examples 55 to 72, characterized by the following steps:
[0511] the electrical heart signals, including premature
extrasystoles, are detected at an extracardiac, preferably
epicardial or thoracic or intracavitary level, by means of a
plurality of detection electrodes implanted in various parts of the
heart or in the vicinity thereof, [0512] it is determined whether a
given extrasystole is dangerous, for example by being premature or
of ventricular origin, [0513] and a stimulating train is
instantaneously transmitted in the region of at least one
stimulating electrode. [0514] 74. Process according to any one of
example 73 wherein the device comprises stimulating electrodes in
various intra- or juxta-cardiac locations and stimulation is
simultaneously carried out from a plurality or all of these
electrodes to induce the fused QRS complexes blocking the still
non-refractory myocardial spaces before the arrival of detected
extrasystole propagation. [0515] 75. Process according to either
example 73 or example 74, wherein sequential recording and storing
of the extrasystoles, in particular the extrasystoles which are
considered to be dangerous, is carried out and, in the event of
repetition, preventive stimulation, in particular by temporary
acceleration of a stimulation base rhythm is carried out. [0516]
76. Process according to any one of examples 55 to 75, wherein
continuous monitoring of the excitability thresholds of the heart
muscle comprising the following steps is carried out: [0517]
inotropic stimulation is carried out by transmitting a pulse train
in such a way that a pulse of the train occurs very shortly after
the end of the refractory period of the heart, [0518] the
stimulation-inducing pulse of the pulse train is identified, [0519]
during the following cardiac cycles, the energy of the stimulating
pulse thus detected is reduced progressively or abruptly to the
level where said pulse of the train becomes ineffective and
therefore subliminal, the following pulse of the train thus causing
stimulation, and the energy of the subliminal pulse is recorded and
thus determines an excitability threshold zone. [0520] 77. Process
according to example 76, characterized by the following steps:
[0521] it is checked that the threshold or the excitability
threshold zone remains substantially stable, [0522] and the energy
of the pulses in the burst is reduced to a value which is lower,
but higher than the excitability threshold, while simultaneously
checking the regular continuation of the stimulated electrical
complexes. [0523] 78. Process according to either example 76 or
example 77 wherein the energy amplitude of the first pulses of a
burst is reduced to a level lower than the excitability threshold,
[0524] it is observed whether or not this subliminal
stimulation-inducing reduction reduces the myocardial excitability
threshold, [0525] and, if this threshold is reduced, the intensity
of the following pulses of the burst is reduced while
simultaneously checking the regular continuation of the stimulated
complexes. [0526] 79. Process according to example 78, comprising
the following steps: [0527] the energy amplitude at which the
stimulating pulse or the stimulating train or a portion of the
train will become subliminal and will no longer generate observable
stimulation is detected, [0528] then the energy amplitude of the
pulse which has become subliminal or the portion of the pulse train
which has become subliminal is increased instantaneously during the
next cardiac cycles. [0529] 80. Process according to example 79,
wherein the energy amplitude of the pulses is progressively
increased in order to determine the new myocardial excitability
threshold relative to the geometric shape and the location of the
electrodes. [0530] 81. Process according to any one of examples 55
to 80, wherein a stimulating pulse or burst is sent inside the zone
MMRZ situated inside the plateau of the contraction curve of the
mechanogram and during which the contraction of the myocardium is
substantially at its peak. [0531] 82. Process according to example
81, wherein the pulse or at least one pulse of a stimulation burst
falls within said zone MMRZ. [0532] 83. Process according to any
one of examples 81 and 82, wherein said zone MMRZ is acquired
automatically. [0533] 84. Process according to example 83, wherein
the infra-cavitary pressure is measured by a sensor and a zone of
maximum pressure is selected in the systolic plateau of the cardiac
mechanogram in which the transmission of a stimulating pulse or
burst is induced. [0534] 85. Process according the example 83,
wherein the local intramyocardial pressure is measured in the
vicinity of a detecting and stimulating electrode. [0535] 86.
Process according to example 85, wherein the myocardial pressure is
detected in the intra-auricular and/or intraventricular septum.
[0536] 87. Process according to example 83, wherein the variation
in the volume of the heart or a part of the heart is measured by
detecting the zone where said volume has reached and maintains its
minimum value. [0537] 88. Process according to any one of examples
81 to 87, wherein the oxygen consumption of the heart is measured
and the zone of maximum cardiac contraction (MMRZ) is detected by
estimation by detecting, during one or more previous cycles, the
relative position, in the cycle and/or in the mechanogram, of the
pulse or the pulse of a burst which has generated
post-extrasystolic potentiation (PESP) without a significant
increase in energy consumption. [0538] 89. Process according to any
one of examples 55 to 88, wherein: [0539] information to relating
to a patient's electrocardiogram, including the heart rhythm, is
acquired, [0540] information relating to the patient's hemodynamic
performance is acquired; [0541] and this information is used to
simulate the effect of prolonged inotropic paired or coupled
stimulation. [0542] 90. Process according to example 89 wherein
said acquired information relating to the patient's hemodynamic
performance is additionally compared to the simulated effect on
said performance of an inotropic paired stimulation. [0543] 91.
Process according to either example 89 or example 90, wherein the
information is acquired and compared cycle by cycle. [0544] 92.
Process according to any one of examples 89 to 91, wherein at least
one of the following parameters relating to cardiac contraction is
measured: [0545] gradient (dp/dt) of the phases of ascent and/or
descent of the intracavitary and/or intramyocardial pressure;
[0546] duration of the systolic pressure plateau, corresponding to
systolic ejection; [0547] duration of the systole (cardiac
contraction); [0548] duration of the diastole (filling phase);
[0549] ratio between diastole and systole durations; [0550] quality
of the diastole, in particular filling depression or speed and
amplitude of the fast and slow phases; [0551] electromechanical
coupling (period separating the beginning of a QRS complex from the
beginning of the mechanical systole which it causes); [0552] shift
between the local intramyocardial contraction curve and the global
ventricular intracavitary contraction curve. [0553] 93. Process
according to any one of examples 89 to 92, wherein information
relating to the electrocardiogram and to the hemodynamic
performance of a simulation of inotropic paired or coupled
stimulation is compared with corresponding information acquired
during a subsequent identical or similar actual inotropic
stimulation. [0554] 94. Process according to any one of examples 89
to 93, wherein a threshold level of values of information on the
simulated hemodynamic performance of the patient is acquired or
calculated and, if the threshold is exceeded, an identical or
similar inotropic paired or coupled actual stimulation is
triggered. [0555] 95. Process according to any one of examples 89
to 94, wherein the information relating to the patient's
electrocardiogram and to the patient's hemodynamic performance is
acquired at different rhythms, in particular rhythms which increase
or decrease by increments or progressively. [0556] 96. Process
according to any one of examples 89 to 95, wherein there are used
means which are sensitive to said acquisition means arranged so as
to simulate the effects of a plurality of inotropic paired or
coupled stimulations at different heart rhythms. [0557] 97. Process
according to any one of examples 89 to 96, wherein said comparison
is effected for a limited number of cycles of the actual inotropic
stimulation and, if the absence of a satisfactory hemodynamic
performance level is observed, the current inotropic stimulation is
terminated. [0558] 98. Process according to example 97, wherein
said number of cycles is approximately 10 or less, in particular 1,
2 or 3 cycles. [0559] 99. Process according to either example 97 or
example 98 wherein, if an adequate initial increase in hemodynamic
performance is observed, inotropic stimulation is continued and it
is detected whether the initial increase in hemodynamic performance
is maintained and/or still increases progressively for a greater
number of cycles. [0560] 100. Process according to example 99,
wherein said greater number of cycles is at least about 100 cycles.
[0561] 101. Process according to any one of examples 89 to 100,
wherein the effects of cardiovascular target medicaments, which
have previously been administered or are being administered, are
used in the analysis. [0562] 102. Process according to any one of
examples 89 to 101, wherein the differences between the simulation
and stimulation curves are emphasized visually and/or
quantitatively, in particular by superimposition of the curves.
[0563] 103. Process according to any one of examples 55 to 102,
wherein the cardiac mechanogram is acquired, in particular until
the appearance of a cycle which is long enough to obtain a good
myocardial contraction, and a stimulating pulse or burst is then
transmitted at an instant within the plateau of the mechanogram
curve (MMRZ), in particular just before the end of the electrical
refractory zone (ERZ), and stimulation is then carried out
immediately after the end of the electrical refractory zone which
will cause a new electrical refractory zone. [0564] 104. Process
according to any one of examples 55 to 103, wherein there is
defined a first threshold of increase in global hemodynamic
performance/min and/or per cardiac contraction, in particular the
cardiac output, said threshold being equal to at least 15% or
preferably 25% of the performance prior to treatment, and the
stimulation parameters are adjusted until at least said threshold
value is obtained. [0565] 105. Process according to example 104,
wherein, if the increase according to said first threshold value is
not obtained during a period of approximately 1 to 10 contractions,
the treatment is stopped. [0566] 106. Process for treating acute or
severe heart failure wherein: [0567] the heart rhythm and, in
particular, the interval between at least the last two waves R
(induced or spontaneous) of a cardiac cycle which has just been
completed are automatically acquired, [0568] the duration of the
electrical refractory period (ERZ) following the last wave R of
said cycle is determined, preferably continually, [0569] at least
one stimulating pulse and preferably a stimulating pulse burst is
sent substantially without delay at the end of the refractory
period (ERZ), the duration of the burst being such that, in view of
the pulse repetition interval in the burst, a stimulating pulse of
the burst is sent to the heart substantially without delay after
the end of the refractory period, and [0570] these steps are
repeated for a series of at least three contractions if an initial
improvement in cardiac performance is observed, [0571] and, in the
absence of an improvement, the process is automatically stopped.
[0572] 107. Process according to example 106, wherein the total
mechanical performance of the heart, in particular its blood flow
and/or the variation in ventricular volume is compared, on the one
hand, before carrying out the steps of the process and, on the
other hand, after carrying out the steps of the process and, if the
increase in heart performance is greater than 15%, the steps of the
process are carried out again. [0573] 108. Process for cardiac
resuscitation in a patient suffering from severe or critical heart
failure wherein: [0574] the heart rhythm and, in particular, the
interval between at least the last two waves R (induced or
spontaneous) of a cardiac cycle which has just been completed is
automatically acquired, [0575] the duration of the electrical
refractory period (ERZ) following the last wave R of said cycle is
determined, preferably continually, [0576] at least one stimulating
pulse and preferably a stimulating pulse burst is sent
substantially without delay at the end of the refractory period
(ERZ), the duration of the burst being such that, in view of the
pulse repetition interval in the burst, a stimulating pulse of the
burst is sent to the heart substantially without delay after the
end of the refractory period, and [0577] these steps are repeated
for a series of at least three contractions if an initial
improvement in cardiac performance is observed, and [0578] these
steps are repeated at least until an at least progressive
improvement in detectable cardiac performance is achieved. [0579]
109. Process according to any one of examples 106 to 108, also
comprising the steps of the process according to example 56. [0580]
110. Process for in vitro stimulation of cells intended to be
implanted in the heart, said process comprising the following
steps: [0581] obtaining and cultivating, in vitro, regeneration
cells, preferably in the form of small groups or confluent
cultures, so as to be in mutual contact; [0582] placing the
confluent cells in electrically conductive contact with one another
and optionally with the cells of a previously taken myocardial
tissue and with an electrical stimulation device, [0583]
periodically sending electrical pulses to said cultivated cells;
[0584] detecting the electrical depolarization responses of the
cells and/or membrane potentials, and/or electrical refractory
zones. [0585] 111. Process according to example 110 wherein the
stimulation is a simple electrical stimulation at a rhythm
preferably approximating a normal heart rhythm, followed after an
initial period by a paired or coupled stimulation according to any
one of examples 1 to 20, once the groups of cells in culture are
synchronized so as to manifest an electrical refractory period, in
particular a period relatively close to that of the cells of the
heart intended to receive the cells.
[0586] 112. Process according to any one of examples 110 and 111,
wherein the cells have been modified so as to over-express
telomerase or Sir2 protein. [0587] 113. Process for preparing
living cells, in particular vegetable, animal and human cells,
which can be reimplanted prophylactically or therapeutically,
wherein a nucleus of a dedifferentiated cell is transported in an
oocyte, preferably an unfertilized or recently fertilized oocyte
from a homologous or heterologous mammal, previously preferably
completely or partially freed of its nucleus, so as to induce a
stage of mitosis of the transferred nucleus, in that this nucleus
is removed during the mitosis and before the end of it, then this
nucleus which is partially dedifferentiated in mitosis at this
stage is introduced into a cell, preferably after some part or the
totality of its nucleus or nuclei have been removed from it, so as
to induce and terminate the differentiating nuclear division
thereof and to form a cell strain or a tissue at a less advanced
stage of differentiation than said differentiated cell. [0588] 114.
Process according to any one of examples 110 to 113 wherein the
transferred nucleus is extracted at the metaphase stage of the
first mitosis. [0589] 115. Process according to any one of examples
110 to 113, wherein the transferred nucleus is extracted at the
anaphase stage of the first mitosis. [0590] 116. Process according
to any one of examples 110 to 113, wherein the transferred nucleus
is removed at the prophase stage of the first mitosis. [0591] 117.
Process according to any one of examples 110 to 113, wherein the
transferred nucleus is removed at the telophase stage of the first
mitosis. [0592] 118. Process according to any one of examples 110
to 117, wherein a nucleus of myocardial, muscle or auto-rhythmic
cardiac cell, in particular sinusal cells from the Tawara's node or
fibers from the His' bundle or Purkinje bundle are transferred into
the oocyte. [0593] 119. Process according to example 118, wherein
the removed nucleus is introduced, before the end of its
intra-oocyte mitosis, into a myocardial or muscle cell, which is
preferably freed of its nucleus or some or all of its nuclei.
[0594] 120. Process according to either example 118 or example 119,
wherein the partially dedifferentiated cells obtained are
subjected, preferably after or during the cell multiplication
culture thereof after the formation of a confluent assembly, to
periodic electrical stimulation of the cardiac stimulation type, in
particular according to any one of examples 22 to 24. [0595] 121.
Process according to example 120, wherein said cells are subjected
to coupled or paired electrical stimulation in which this pulse
without a contractile effect is sent just after the end of the
electrical refractory period of the cells in culture. [0596] 122.
Process according to example 120, wherein said cells are subjected
to electrical stimulation in cycles comprising a first stimulating
pulse and, [0597] toward the end of the refractory period, a pulse
train, so that at least one of the pulses of the train falls just
after the end of the electrical refractory period of the cells and
during their mechanical refractory zone of maximum contraction.
[0598] 123. Process according to any one of examples 55 to 109
wherein, before carrying out the steps of the process, myocardial
or muscle or similar cells, in particular cells obtained by a
process according to any one of examples 100 to 112, are implanted
in the heart. [0599] 124. Process wherein the cells obtained by the
process according to any one of examples 110 to 123 are implanted
in the region of the auricular myocardium, in particular in the
case of a patient suffering from auricular fibrillation. [0600]
125. Process according to any one of examples 113 to 117 wherein
nuclei or parts thereof of cells of pilose follicles and/or
melanocytes allowing regeneration of hair and/or the coloring
thereof are transferred into the oocyte. [0601] 126. Arterial
segment or stent, in particular with a coronary, aortic, carotid,
renal or femoral target, comprising a structure which is coated or
colonized by cells obtained by the process according to any one of
examples 110 to 122. [0602] 127. Physiological arterial segment or
stent consisting of living, auto-contractile and elastic, in
particular autologous, cells, cultivated according to any one of
examples 110 to 122. [0603] 128. Arterial segment or stent
according to either example 126 or example 127 shaped in the manner
of an arterial stent arranged so as to be introduced into an
arterial lumen. [0604] 129. Segment or stent according to examples
126 to 128, comprising means for electrical stimulation of the
arterial type, coordinated with the ventricular diastole, of said
cells of the segment. [0605] 130. Segment or stent according to any
one of examples 126 to 129, comprising at least one stimulating
and/or detecting electrode. [0606] 131. Segment or stent according
to example 130, wherein the stimulating and/or detecting electrode
has been introduced into the cell culture so as to be surrounded by
said living cells. [0607] 132. Segment or stent according to any
one of examples 126 to 131 comprising a sensor, in particular for
measuring oxygen saturation and/or metabolic parameters and a
detecting or stimulating electrocardiographic sensor. [0608] 133.
Segment or stent according to any one of examples 126 to 132,
comprising a plurality of electrodes arranged so as to obtain the
variations in local electrical impedance. [0609] 134. Arterial
segment or stent according to any one of examples 126 to 133 having
a structure, in particular in expansible meshes supporting
different cell layers, such as an endoartery, myoartery and
periartery structure, said structure allowing a spontaneous
increase with progressive widening of its lumen and creation of
vascularization which nourishes, in particular, the myoarterial
portion. [0610] 135. Segment according to any one of examples 126
to 134, wherein the structure is produced from at least one of the
following materials: PLGA, collagen, globin. [0611] 136. Arterial
stent without living cells having a structure which is radially
expansible but sufficiently rigid to keep the arterial aperture
open at least in systole, which is optionally biodegradable or
removable by a catheter and capable of receiving a physiological
stent according to any one of examples 126 to 135. [0612] 137.
Tissue block for implantation in or on the heart and comprising a
segment according to any one of examples 127 to 135, surrounded by
its functional block of peripheral vasculo-myocardial tissue
provided with arteries, arterioles, and capillary and venous
network, which can be sewn or anchored in or on the recipient's
myocardium. [0613] 138. Biological cardiac pacemaker comprising
partially dedifferentiated cardiac auto-rhythmic cells or tissues
according to any one of examples 110 to 122, which is preferably
autologous or homologous, originates from the recipient's organism
and is intended to be implanted in the heart or in a defective
region of the heart.
* * * * *